Microsomal P450-mediated monooxygenase activity supported by NADPH requires an interaction between flavoprotein NADPH-cytochrome P450 reductase and cytochrome P450. These proteins have been identified as the simplest system (with the inclusion of a phospholipid (PL) component) that possesses monooxygenase function; however, little is known about the organization of these proteins in the microsomal membrane. Although reductase and P450 are known to form a 1:1 functional complex, there exists a 10- to 20-fold excess of P450 over the reductase. This raises several questions including "How are the enzymes of the P450 system organized in the microsomal membrane?" and "Can one P450 enzyme affect the functional characteristics of another P450?" This review summarizes evidence supporting the potential for enzymes involved in the P450 system to interact, focusing on the interactions between reductase and P450 and interactions between multiple P450 enzymes. Studies on the aggregation characteristics of P450 as well as on rotational diffusion are detailed, with a special emphasis on the potential for P450 enzymes to produce oligomeric complexes and to suggest the environment in which P450 exists in the endoplasmic reticulum. Finally, more recent studies describing the potential for multiple P450s to exist as complexes and their effect on P450 function are presented, including studies using reconstituted systems as well as systems where two P450s are coexpressed in the presence of reductase. An understanding of the interactions among reductase and multiple P450s is important for predicting conditions where the drug disposition may be altered by the direct effects of P450-P450 complex formation. Furthermore, the potential for one P450 enzyme to affect the behavior of another P450 may be extremely important for drug screening and development, requiring metabolic screening of a drug with reconstituted systems containing multiple P450s rather than simpler systems containing only a single form.