The primary immunodeficiency diseases are a relatively rare group of congenital disorders that are linked by the expression of an excessive number, duration, or severity of infections. The clinical features of most of the primary immunodeficiency diseases have been well described by astute physicians over several decades and have provided important clues to our basic understanding of human immunology. In contrast, the genetic basis and potential life-saving therapies for many of these disorders have been established only over the past few years. These recent advances have resulted in the prognosis of many of these disorders being largely dependent on their rapid recognition and treatment. Increased awareness of the differentiating epidemiologic, clinical, laboratory and genetic features of these diseases hold the promise of both furthering our understanding of basic human immunology and providing improved care for this challenging group of patients.