The term activation is used to designate biochemical and functional changes that are induced in macrophages by a variety of stimuli, including interaction with microbial products, synthetic substances, immunoglobulins of different classes, and factors released by lymphocytes. The changes observed comprise an increased capacity to destroy intracellular microorganisms and non-microbial target cells as well as the stimulation of biochemical pathways leading to the release of enzymes and the generation of various toxic compounds. Activation may thus be viewed as a process aimed at recalling those metabolic functions that are necessary for killing, when phagocytosis has failed to evoke them. The increased microbicidal capacity of activated macrophages is linked to the production of oxygen intermediates, as illustrated by the study of macrophage toxicity for certain intracellular protozoan parasites. Scavengers of oxygen metabolites inhibit parasite killing in macrophages; on the contrary, agents that stimulate the production or utilization of such intermediates enhance the microbicidal effect of phagocytes. Several mechanisms enable microorganisms to survive within macrophages. In some instances, intracellular survival appears to depend on the capacity of microorganisms to be endocytized without awakening the host cell oxidative machinery. In addition, the endowment of microorganisms in endogenous enzymatic scavengers of oxygen metabolites may play a role in promoting intracellular survival. These and other mechanisms, such as the property to avoid the harmful effects of lysosomal constituents by inhibiting phagosome-lysosome fusion, or by releasing agents that block the lysosomal enzymatic machinery, may explain why certain microbes are able to survive within activated macrophages.