The constitutive androstane receptor (CAR), a member of the NR1I group of nuclear hormone receptors, has been implicated in regulating the expression of genes that are critical in xenobiotic and endobiotic metabolism, uptake and elimination as well as genes involved in various other physiological processes. Hence, functional variation in CAR associated with its expression and/or activity can influence the transcriptional activation of its target genes and could contribute to the observed variation in drug response and toxicity. Moreover, coadministration of agents that are also CAR activators contributes to clinically relevant drug-drug interactions in patients receiving certain combination therapies. This review will discuss the functional significance of known genetic variants in CAR and the most common alternatively spliced isoforms of CAR. We will also discuss the influence of gender and ethnicity on CAR and its target genes. Although genetic polymorphisms in CAR may have an indirect effect on drug disposition, understanding the association of genetic polymorphisms in CAR with the expression of its target genes might help us to better understand the molecular mechanisms underlying the interindividual variation in drug disposition in addition to drug-drug interactions.