The synapse has dominated the conceptual model of neurotransmission; other mechanisms, such as neuromodulation, have been considered to support and complement synaptic transmission. In this commentary, the conceptual framework considers synaptic transmission as one of several mechanisms of neurotransmission. One of these is nonsynaptic diffusion neurotransmission (NDN), which includes both the diffusion of neurotransmitters and other neuroactive substances through the extracellular fluid to reach extrasynaptic receptors, and the diffusion of substances such as nitric oxide through both the extracellular fluid and cellular membranes to act within the cell. The possible roles of NDN in mass, sustained functions such as mood, sleep and brain "tone", as well as in various other functions, such as in long term potentiation, at the retinal, lateral geniculate nucleus and visual cortex levels of the visual system, in recovery from brain damage and in neuropharmacology, are explored.