Protein kinase C (PKC) has been identified in islets of Langerhans and insulin-secreting tumour cells. Diacylglycerols (DAGs, the endogenous PKC activators) are generated in response to insulin secretagogues, although nutrient and non-nutrient secretagogues generate DAGs of different compositions and of different potencies as PKC activators. Exogenous activators of PKC stimulate insulin secretion from B cells, but attempts to define a physiological role for PKC by using inhibitors of this enzyme have produced ambiguous results. However, in studies using PKC-depleted B cells the loss of PKC activity does not inhibit glucose-induced insulin secretion, but markedly reduces responses to cholinergic agonists. These observations are supported by measurements of PKC activation which suggest that the enzyme is activated by cholinergic agonists, but not by nutrient secretagogues. Currently available experimental evidence therefore suggests that activation of PKC is not essential for nutrient-induced insulin secretion, but is required for the expression of a normal secretory response to cholinergic neurotransmitters.