This review examines the role of acetylcholine in synaptic plasticity in archi-, paleo- and neocortex. Studies using microiontophoretic application of acetylcholine in vivo and in vitro and electrical stimulation of the basal forebrain have demonstrated that ACh can produce long-lasting increases in neural responsiveness. This evidence comes mainly from models of heterosynaptic facilitation in which acetylcholine produces a strengthening of a second, noncholinergic synaptic input onto the same neuron. The argument that the basal forebrain cholinergic system is essential in some models of plasticity is supported by studies that have selectively lesioned the cholinergic basal forebrain. This review will examine the mechanisms whereby acetylcholine might induce synaptic plasticity. It will also consider the neural circuitry implicated in these studies, namely the pathways that are susceptible to cholinergic plasticity and the neural regulation of the cholinergic system.