Like dioxin, some polychlorinated biphenyl (PCB) congeners produce toxicity by binding to an aryl hydrocarbon (Ah) receptor. Other PCB congeners that have little or no activity at the Ah receptor have been shown to accumulate in the brain following in vivo exposure and decrease dopamine content. Subsequent research has found that non-dioxin-like PCBs also interfere with calcium homeostatic mechanisms and intracellular second messenger systems in vitro in neuronal cultures and brain subcellular fractions. The biological significance of these effects of PCBs in nervous system preparations is not known, although a number of calcium-dependent processes are important for nervous system function and development. Structure-activity relationship (SAR) studies based on measures of PCB-induced alterations in protein kinase C (PKC) translocation and Ca2+-buffering indicate that congeners with chlorine substitutions at the ortho-position are active in vitro, while non-ortho congeners are relatively inactive. Subsequent research has found that chloride substitution patterns that favor non-co-planarity are associated with activity in nervous system preparations. Recent in vivo studies in adults have shown that repeated exposure to a PCB mixture Aroclor 1254 increases translocation of PKC and decreases Ca2+-buffering in the brain. Increased levels of ortho-substituted non-coplanar PCB congeners were observed in the brains of Aroclor 1254-treated animals relative to vehicle controls. Current research is focusing on the possibility that PCB-induced alterations in calcium homeostasis and intracellular second messengers may be related to the developmental neurotoxicity of PCBs.