Following the initial demonstration of phosphorylation of endogenous brain proteins (Johnson et al., 1971), two decades of work have shown that this biochemical mechanism represents one of the most important means by which extracellular signals are transduced into changes in neuronal functions. Evidence discussed in this review shows that neural cells contain a plethora of protein kinases, protein phosphatases, and phosphorylated proteins and that many of these systems appear essential for the regulation of cell functions as diverse as membrane excitability, neuronal secretory processes, cytoskeletal organization, neuronal morphology, and cellular metabolism. Moreover, there exists intricate functional relationships between many of the neuronal protein phosphorylation systems, which allow "cross-talk" between distinct signals to take place in various brain cells. The properties of protein phosphorylation systems allow these regulatory systems to influence events taking place on a microsecond scale (e.g., neurotransmitter release) and events lasting for hours and days (e.g., LTP). Our present knowledge concerning neuronal protein phosphorylation has also allowed studies to be initiated regarding the possible involvement of protein phosphorylation in various clinical disorders affecting signal transduction and brain function. It seems safe to predict that continued studies of neuronal protein phosphorylation systems will continue to improve our understanding of the anatomical, physiological, and pharmacological basis for nervous system function in both health and disease.