At the heart of the immune system is the ability to distinguish between self and nonself. Virtually every body cell carries distinctive molecules that identify it as self.

The body's immune defenses do not normally attack tissues that carry a self marker. Rather, immune cells and other body cells coexist peaceably in a state known as self-tolerance. But when immune defenders encounter cells or organisms carrying molecules that say "foreign," the immune troops move quickly to eliminate the intruders.

Any substance capable of triggering an immune response is called an antigen. An antigen can be a virus, a bacterium, a fungus, or a parasite, or even a portion or product of one of these organisms. Tissues or cells from another individual, except an identical twin whose cells carry identical self-markers, also act as antigens; because the immune system recognizes transplanted tissues as foreign, it rejects them. The body will even reject nourishing proteins unless they are first broken down by the digestive system into their primary, non-antigenic building blocks.

An antigen announces its foreignness by means of intricate and characteristic shapes called epitopes, which protrude from its surface. Most antigens, even the simplest microbes, carry several different kinds of epitopes on their surface; some may carry several hundred. However, some epitopes will be more effective than others at stimulating an immune response.

In abnormal situations, the immune system can wrongly identify self as nonself and execute a misdirected immune attack. The result can be a so-called autoimmune disease such as rheumatoid arthritis or systemic lupus erythematosus.

In some people, an apparently harmless substance such as ragweed pollen or cat hair can provoke the immune system to set off the inappropriate and harmful response known as allergy; in these cases the antigens are known as allergens.