The term empiric is defined, and its implications in the treatment of infectious diseases and the selection of β-lactam antibiotics are discussed. Some changes in the choice of empiric therapy during the last half-century are brought out by a discussion of therapy for selected infections. For some infections the changes (if any) have been only minor; for others, however, the changes have resulted in a progressive decline in mortality, a shortening of the course of the disease, and the reduction or elimination of complications. Among the diseases discussed are seborrheic dermatitis, malaria, syphilis, typhoid fever, pneumonia, bacterial endocarditis, and bacterial meningitis.