Transactions between individuals and their physical settings involving consciousness-altering drugs are examined. Research has gradually expanded outward from the individual and the drug to include the social and, finally, the physical context of drug use and misuse. Similarly, theory has evolved from simple unidirectional causal tenets to complex multidirectional contextual tenets. Research to date is sparse and does not live up to the ambitious vision of current theoretical views, but some results are striking and provocative. The review is framed in terms of physical scale (macro-, meso-, and microenvironments) and specificity (from molecular features of a setting to molar environmental characteristics such as stimulation level). Three temporal phases are considered: the development, maintenance, and cessation of substance misuse. The paucity of empirical research combined with the potential importance of environmental factors means that many challenging questions remain for a new generation of researchers.