In this study, the effect of alpha-MSH on tyrosinase activity was compared in epidermal and hair follicular melanocytes of mice. It had no effect on epidermal tyrosinase activity in dorsal skin from neonatal non-agouti black mice (C57BL/6J) in both in-vivo and in-vitro experiments. Theophylline and 8-bromocyclic (c)AMP were similarly without effect in in-vitro experiments. In-vivo administration of alpha-MSH and theophylline for 7 days was also without effect on epidermal tyrosinase activity in ear skin of adult non-agouti mice, and the same was true for alpha-MSH in wild-type agouti mice. Activation of the epidermal melanocytes in the non-agouti and wild-type agouti mice with ultraviolet radiation also failed to bring about a response to alpha-MSH and to theophylline in the case of the former. No tyrosinase activity was detected in the epidermis of viable yellow mice (C3H-HeAvy), but, as shown previously, tyrosinase activity was present in the hair follicle when the hair was actively growing and was increased in those mice given either alpha-MSH or theophylline. alpha-MSH and theophylline had no such effects on hair follicular tyrosinase activity in the non-agouti mice. The present results suggest that alpha-MSH- and cAMP-dependent mechanisms have little or no importance in the regulation of tyrosinase expression in mouse epidermal melanocytes. alpha-MSH may, however, regulate tyrosinase expression in hair follicular melanocytes, but even in these melanocytes its action may be restricted to mice that express the agouti gene.