Multixenobiotic resistance in aquatic organisms exposed to natural toxins or anthropogenic contaminants is a phenomenon analogous to multidrug resistance in mammalian tumor cell lines tolerant of anti-cancer drugs. Multidrug resistance is commonly due to the elevated expression of transmembrane P-glycoproteins (P-gp) which actively transport a wide variety of structurally and functionally diverse compounds. The purpose of this review is to place aquatic ecotoxicological data in context of the larger multidrug resistance field of study. Information on P-glycoproteins structure, mechanism of transport, and substrate specificity gained through traditional mammalian and cell culture models is examined in conjunction with recent work on aquatic species exposed to xenobiotics both in the field and in the laboratory. The physiological function of P-glycoproteins is explored through studies of gene knockout models and expression patterns in normal tissues and tumors. The effect of xenobiotic exposures on P-gp activity and protein titer is examined in wild and captive populations of aquatic invertebrates and vertebrates. Substrate overlap and evidence of co-expression of phase I detoxification enzymes (e.g. cytochromes P450) and P-gp are presented. The role of P-gp chemosensitizers as environmental pollutants and the ecotoxicological consequences of P-gp inhibition are highlighted. The overwhelming evidence suggests that P-glycoproteins provide aquatic organisms with resistance to a wide range of natural and anthropogenic toxins.