This investigation examined if lithium, the primary therapeutic treatment for bipolar affective disorder, modulated the levels of selected signal transduction proteins in PC12 cells. Nerve growth factor (NGF) induced differentiation of PC12 cells, and after 12 days of NGF treatment there were large increases in the levels of the heterotrimeric G protein subunits αo1, αi1, β, and αs, small increases in those of αi2 and αq, and a slight decrease in that of αo2. Lithium (1 mM, equivalent to the therapeutic concentration) selectively reduced NGF‐induced increases in levels of G protein subunits, generally having the greatest inhibition on those that were increased the most by NGF. Lithium at 5 mM had greater inhibitory effects than 1 mM lithium on NGF‐induced increases in levels of G proteins, but neither concentration of lithium affected the induction of the cytoskeletal protein β‐tubulin. Examination of other proteins involved in signal transduction revealed that 12 days of NGF treatment increased the level of protein kinase C‐α, but not those of the β, ε, or ζ subtypes, and did not alter the levels of β, γ, or δ phospholipase C. Pretreatment with lithium inhibited the increase in content of protein kinase C‐α induced by NGF but had little effect on the proteins not responsive to NGF except for decreasing the levels of protein kinase C‐ε. The inhibitory effect of lithium was found not to be due to inhibition of NGF‐induced tyrosine phosphorylation, which was unaffected by 5 mM lithium, or to inositol depletion. In summary, use of the dynamic system of NGF‐induced PC12 cell differentiation provided a sensitive model in which to identify signal transduction proteins that were influenced by lithium treatment. The large changes caused by a therapeutically equivalent concentration of lithium lend support to the proposal that the selective inhibitory effects of lithium on subtypes of G proteins and protein kinase C may be important therapeutic targets.