This review attempts to organize the different aspects of nicotinic transmission in the context of nonsynaptic interactions. Nicotinic acetylcholine receptors (nAChRs) dominantly operate in the nonsynaptic mode in the central nervous system despite their ligand-gated ion-channel nature, which would otherwise be better suited for fast synaptic transmission. This fast form of nonsynaptic transmission, most likely unique to nAChRs, represents a new avenue in the communication platforms of the brain. Cholinergic messages received by nAChRs, arriving at a later phase following synaptic activation, can interfere with dendritic signal integration. Nicotinic transmission plays a role in both neural plasticity and cellular learning processes, as well as in long-term changes in basic activity through fast activation, desensitization of receptors, and fluctuations of the steady-state levels of ACh. ACh release can contribute to plastic changes via activation of nAChRs in neurons and therefore plays a role in learning and memory in different brain regions. Assuming that nAChRs in human subjects are ready to receive long-lasting messages from the extracellular space because of their predominantly nonsynaptic distribution, they offer an ideal target for drug therapy at low, nontoxic drug levels.