This is largely a history of attempts from approximately 1960 until about 1980-81 to understand the mechanisms by which neutrophils are activated by chemotactic factors to induce chemotaxis and granule secretion. As such, it deals with the growth of our knowledge of neutrophil chemotactic factors and their receptors; the importance and role of cation fluxes, especially Ca2+, microfilaments and microtubules, membrane potential, cyclic nucleotides, and the start of our recognition of the importance of arachidonic acid and phospholipid metabolism and protein phosphorylation. In a very real sense this is a history of the origins of our present realization that reactions and functions which had been considered specific to the neutrophil are to be thought of as similar or identical to general biological and physiological processes such as muscle contraction, cellular secretion, etc.