The effect of α-melanocyte-stimulating hormone (α-MSH) on protein kinase C activity and distribution was investigated in murine B16 F1 melanoma cells, α-MSH was found to induce an increased association of protein kinase C (PKC) activity with the particulate fraction of the cells, with an associated loss of enzyme activity from the soluble fraction. The peak response to α-MSH occurred between 20 and 60 min of incubation time, and enzyme activities redistributed to those seen in the control cells over the following 12 to 24 h. The average response to α-MSH (1 nmol/l) was an approximate 2·5-fold increase in the percentage of enzyme activity associated with the membrane within 1 h of exposure to α-MSH; the particulate enzyme activity represented 19·2 ± 4·4% of total activity in the absence of α-MSH and 50·7 ± 4·7% (means ± s.e.m., n = 9, P < 0·005) in the presence of α-MSH (1 nmol/l). Cells which had a relatively small percentage of their PKC activity on the membrane initially were significantly (P < 0·01) more responsive to α-MSH stimulation than cells which initially had a relatively large percentage of PKC activity on the membrane. The association of PKC activity with the membrane showed some evidence of being dose-related to α-MSH. This is the first report, to the best of our knowledge, of α-MSH activating PKC. Journal of Endocrinology (1992) 133, 333–340