Previous studies have reported conflicting results in terms of acute effects of cannabis in man. Independently of other factors, such discrepancy may be attributable to the different cannabis use history of study volunteers. It is thought that regular cannabis users may develop tolerance to the effects of acute cannabis administration. Here we systematically review all studies examining the effects of single or repeated cannabinoid administration in man as a function of previous cannabis exposure. Research evidence tends to suggest that the acute effects of single cannabinoid administration are less prominent in regular cannabis users compared to non-regular users. Studies of repeated cannabinoid administration more consistently suggest less prominent effects upon repeated exposure. Cognitive function is the domain showing the highest degree of tolerance, with some evidence of complete absence of acute effect (full tolerance). The acute intoxicating, psychotomimetic, and cardiac effects are also blunted upon regular exposure, but to a lesser extent (partial tolerance). Limited research also suggests development of tolerance to other behavioral, physiological, and neural effects of cannabis.