Organic anion transporters (OATs), which belong to the superfamily SLC22A, are key determinants in the absorption, distribution, and excretion of a diverse array of environmental toxins, and clinically important drugs, and, therefore, are critical for the survival of mammalian species. Alteration in the function of these drug transporters plays important roles in intra- and inter-individual variability of the therapeutic efficacy and the toxicity of many drugs. As a result, the activity of OATs must be under tight regulation so as to carry out their normal functions. This review article highlights the recent advances from our laboratory as well as from others in delineating the short-term regulation of OATs. These advances provide important insights into strategies to maximize therapeutic efficacy in drug development.