Even the most vigilant fishkeepers will, at one time or another, have to deal with disease in the fishtank.  Before panicking, understand that as an aquarist you wear the hat of a chemist AND a doctor.  Just approach the situation methodically, and you'll be able to handle the outbreak in the best scenario possible.  Recognizing illness in your puffer as early as possible is important.  Your observations of disease indicators such as abnormal behavior, poor coloration, and external abnormalities will allow you to diagnose the disease or illness early.  As with humans, the quicker you can catch the ailment and treat it, the better the chance of recovery for your puffer.  Once the illness is properly diagnosed, treatment can begin.  Although treating your puffer may take a little research on your part, it will be in vain if you don't diagnose the disease early enough.  You should be familiar with the general behavior of your puffer's species, as well as the quirks of the individual fish.  Although the latter only comes with time, your puff's behavior will almost never be completely anomalous for its species.  Take an holistic approach to diagnosing and treating your puffer.  Consider every option before arriving at a conclusion.  Be vigilant, but use moderation.  While you don't want to be a hypochondriac every time your fish acts or seems a bit odd, you don't want to ignore prolonged oddities.
Abnormal behavior can manifest itself in many different ways.  Normally, puffers have a ravenous appetite, and will eat almost as much as you can feed them.  One of the first signs that your puffer may be ill is its refusal to eat.  Remember though, that certain puffers prefer some foods over others, even when of the same species.  One of my green puffers doesn't consider bloodworms a big deal, while the other voraciously consumes them.  Swimming patterns can be indicators as well.  The common "up and down" swimming pattern of aquarium puffers can sometimes be an indicator of illness or discomfort.  (although sometimes it is a "caged animal" behavior, much like a tiger at the zoo) Take special note of things such as rapid ventilation, surface breathing, scraping against objects, or shimmying.  Cock-eyed swimming is also an indicator.  Although puffers will manipulate their axis to gain an advantageous angle on food, unbalanced swimming is definitely bad.  Improper ballast is a sure fire indicator of infection.  Inactivity could be another indicator.  Again, be familiar with your puffer's species.  Hopefully your puffer was introduced into your tank healthy, and you have seen how it normally moves and appears in the aquarium.  Get to know your fish, and you'll realize when something is awry.
Poor coloration in your puffer is dependent upon its species.  You should know the range of coloration for your species.  Additionally, take note that puffers tend to express themselves with coloration as well.  If you have a species of puffer with a white belly, it should always be white.  Sometimes rings or spots will develop.  This should catch your attention.  For the sake of curbing the hypochondria that can easily arise when keeping puffers, don't worry if your fish develops a temporary "grey line" where its dorsal coloration meets its underbelly.  Although this is a stress indicator (stress line), you need not worry as long as it is only temporary.
External abnormalities are often the most obvious indicator that your puff is sick.  It becomes quite clear something is wrong when your fish exhibits clamped gills, damaged fins, cuts and scrapes, or signs of parasitic infection.  In some cases these abnormalities are preceded by the former two indicators, so pay special attention to behavior and coloration and you'll have more to go on when diagnosing your puffer.

    Once you realize something is wrong with your puffer, you can begin diagnosing the ailment.  Since there are several main areas of causation, understanding the origin of the disease or illness is probably the best place to start.  In the aquarium, there are basically six factors to consider:
 

An Environmental cause of illness is exactly as it sounds.  I refer to it as an illness simply because it is usually chemical in nature.  That is, your puffer is ill either because of unfavorable water conditions, or some toxin which has found its way into your tank.  Sometimes it is as simple as temperature.  As you will see later, checking ALL water conditions is vital at this point. Information on these environmental illnesses are included in the Pathogenic Database.

Parasitic infection of your puffer is fairly self explanatory as well.  There exists in nature (and unfortunately in aquaria) a myriad of different organisms looking to feed on your fish as a parasite.  Parasites find their way into our tanks by way of fish, plants, nets, and food.  Quarantining new arrivals and live food may be time consuming, but doing this is much less of a hassle than treating your sick puff.

Viral and bacteriological agents find their way into your tank in much the same way as parasites do.  Many bacteria are present in your tank at this moment, but luckily nature has given your fish ways to protect itself from such hazards.  At times of stress or illness, these micro-parasites will often take advantage of your puffer's fragile state.

Nutritional deficiencies are perhaps the easiest area to treat.  Varying your puffer's diet easily prevents it from falling to malnutrition.  You can read about this in the section of Puffernet dealing with Holistic Care for your puffer.

Stress-related origins of disease stem from the weakened state of your puffer's immune system.  This particular origin of disease is interwoven with many of the others.  Many times, however, it is stress that weakens the puffers immune system.  This obviously results in some of the preceding factors coming into play more easily.  Click here to view a table showing stress indicators and their possible causes.

The actual diagnosis and treatment of pufferfish (or any fish) can become tricky.  Misdiagnosis can often complicate already stressful tank conditions, not to mention having zero effect on the disease or illness.  Additionally, pufferfish are scaleless, which means certain medications may be worse than the original disease.  Not to worry, the following sections are geared toward treating pufferfish, specifically.  Sometimes the disease is rather obvious and so is the treatment.  If this is the case, you may want to go directly to the Pathogenic Database.  I do recommend reading the next section first, since it details the methodology behind Diagnosis.  This is the most thorough and accurate way to help your puffer.  It's also a good place to start if you aren't 100% sure about your preliminary diagnosis.

Diagnostic Methodology

Diagnostic Flowchart

Pathogenic Database

Rx Database