Direct interaction of cocaine with centrally located monoamine transporters is the primary mechanism underlying its reinforcing properties. It is also often assumed that this drug action is responsible for all the physiological and behavioral effects of this drug. The goal of this review is to challenge this basic mechanism and demonstrate the importance of peripheral actions of cocaine in inducing its initial, rapid neural effects. The use of high-resolution electrophysiological, neurochemical and physiological techniques revealed that the effects of intravenous cocaine at behaviorally relevant doses are exceptionally rapid and transient correlating with strong, quick, and transient increases in blood cocaine levels. Some of these effects are mimicked by cocaine-methiodide, a cocaine analog that cannot cross the blood-brain barrier and they are resistant to dopamine (DA) receptor blockade. Therefore, it appears that rapid neural effects of cocaine result from its direct interaction with receptive sites on afferents of sensory nerves densely innervating blood vessels. This interaction creates a rapid neural signal to the CNS that results in generalized neural activation and subsequent changes in different physiological parameters. This drug's action appears to be independent from cocaine's action on central neurons, which requires a definite time to occur and induce neural and physiological effects with longer latencies and durations. The co-existence in the same drug on two timely distinct actions with their subsequent interaction in the CNS could explain consistent changes in physiological and behavioral effects of cocaine following their repeated use, playing a role in the development of drug-seeking and drug-taking behavior.