A plague ravages the kingdom, setting the adventurers on a quest to find a cure. An adventurer emerges from an ancient tomb, unopened for centuries, and soon finds herself suffering from a wasting illness. A warlock offends some dark power and contracts a strange affliction that spreads whenever he casts spells.
A simple outbreak might amount to little more than a small drain on party resources, curable by a casting of lesser restoration. A more complicated outbreak can form the basis of one or more adventures as characters search for a cure, stop the spread of the disease, and deal with the consequences.
A disease that does more than infect a few party members is primarily a plot device. The rules help describe the effects of the disease and how it can be cured, but the specifics of how a disease works aren't bound by a common set of rules. Diseases can affect any creature, and a given illness might or might not pass from one race or kind of creature to another. A plague might affect only constructs or undead, or sweep through a halfling neighborhood but leave other races untouched. What matters is the story you want to tell.

Sample Diseases

The diseases here illustrate the variety of ways disease can work in the game. Feel free to alter the saving throw DCs, incubation times, symptoms, and other characteristics of these diseases to suit your campaign.

Cackle Fever

This disease targets humanoids, although gnomes are strangely immune. While in the grips of this disease, victims frequently succumb to fits of mad laughter, giving the disease its common name and its morbid nickname: "the shrieks."
Symptoms manifest 1d4 hours after infection and include fever and disorientation. The infected creature gains one level of exhaustion that can't be removed until the disease is cured.
Any event that causes the infected creature great stress--including entering combat, taking damage, experiencing fear, or having a nightmare--forces the creature to make a DC 13 Constitution saving throw. On a failed save, the creature takes 5 (1d10) psychic damage and becomes incapacitated with mad laughter for 1 minute. The creature can repeat the saving throw at the end of each of its turns, ending the mad laughter and the incapacitated condition on a success.
Any humanoid creature that starts its turn within 10 feet of an infected creature in the throes of mad laughter must succeed on a DC 10 Constitution saving throw or also become infected with the disease. Once a creature succeeds on this save, it is immune to the mad laughter of that particular infected creature for 24 hours.
At the end of each long rest, an infected creature can make a DC 13 Constitution saving throw. On a successful save, the DC for this save and for the save to avoid an attack of mad laughter drops by 1d6. When the saving throw DC drops to 0, the creature recovers from the disease. A creature that fails three of these saving throws gains a randomly determined form of indefinite madness, as described later in this chapter.

Sewer Plague

Sewer plague is a generic term for a broad category of illnesses that incubate in sewers, refuse heaps, and stagnant swamps, and which are sometimes transmitted by creatures that dwell in those areas, such as rats and otyughs.
When a humanoid creature is bitten by a creature that carries the disease, or when it comes into contact with filth or offal contaminated by the disease, the creature must succeed on a DC 11 Constitution saving throw or become infected.
It takes 1d4 days for sewer plague's symptoms to manifest in an infected creature. Symptoms include fatigue and cramps. The infected creature suffers one level of exhaustion, and it regains only half the normal number of hit points from spending Hit Dice and no hit points from finishing a long rest.
At the end of each long rest, an infected creature must make a DC 11 Constitution saving throw. On a failed save, the character gains one level of exhaustion. On a successful save, the character's exhaustion level decreases by one level. If a successful saving throw reduces the infected creature's level of exhaustion below 1, the creature recovers from the disease.

Sight Rot

This painful infection causes bleeding from the eyes and eventually blinds the victim.
A beast or humanoid that drinks water tainted by sight rot must succeed on a DC 15 Constitution saving throw or become infected. One day after infection, the creature's vision starts to become blurry. The creature takes a −1 penalty to attack rolls and ability checks that rely on sight. At the end of each long rest after the symptoms appear, the penalty worsens by 1. When it reaches −5, the victim is blinded until its sight is restored by magic such as lesser restoration or heal.
Sight rot can be cured using a rare flower called Eyebright, which grows in some swamps. Given an hour, a character who has proficiency with an herbalism kit can turn the flower into one dose of ointment. Applied to the eyes before a long rest, one dose of it prevents the disease from worsening after that rest. After three doses, the ointment cures the disease entirely.