Alterations in drug transport are a major cause of chemotherapy failures due to nonspecific resistance mechanisms. These mechanisms involve several ABC transporter proteins among which the P-glycoproteins have been the most extensively studied in vertebrates. Increased Pgp expression and/or activity in organisms leads to resistance to many chemically unrelated compounds and therapeutic agents. Such resistance has been observed in cancer and in other diseases due to infectious and parasitic pathogens. Most of the available information on these transporters has been obtained from genetic analyses, although useful data for understanding the cellular mechanisms of such resistance remains limited. As resistance affects several types of organism comparative information on the function and activity of these cellular pumps in various biological environments would be welcome. As such, nematodes represent a possible model. Recent data have been obtained for efflux function and modulation by different molecules in these invertebrates. The observed data are summarized here and the future of these studies is discussed.