M-current is a non-inactivating potassium current found in many neuronal cell types. In each cell type, it is dominant in controlling membrane excitability by being the only sustained current in the range of action potential initiation. It can be modulated by a large array of receptor types, and the modulation can occur either by suppression or enhancement. Modulation of M-current has dramatic effects on neuronal excitability. This review discusses the numerous second messenger pathways that converge on regulation of this current: in particular, two forms of regulation of the M-current, receptor-mediated modulation and the control of macroscopic current amplitude by intracellular calcium. Both types of regulation are discussed with reference to the modulation of single-channel gating properties.