Organic anion transporting polypeptides (OATPs, gene name SLCO) are uptake transporters for a broad range of endogenous compounds and xenobiotics. To investigate the physiological and pharmacological roles of Oatp1a/1b transporters, we generated and analyzed mice lacking all Slco1a/1b genes, and humanized transgenic rescue mice overexpressing human OATP1B1 and OATP1B3 in the liver. Slco1a/1b-/- mice were viable and fertile but suffered from marked conjugated hyperbilirubinemia, likely due to impaired hepatic (re-)uptake of bilirubin-glucuronide (Van de Steeg et al, 2010). These mice also displayed increased plasma levels of unconjugated bile acids. Using Oatp1a/1b and Abcc3 knockout mice and the OATP1B1 and OATP1B3 transgenic mice, we could show that in normal liver Oatp1a/1b, OATP1B1, OATP1B3, and the multispecific sinusoidal export pump Abcc3 drive a detoxification-enhancing liver-blood shuttling loop for bilirubin glucuronide. Within liver lobules, this shuttle allows flexible transfer of bilirubin- and probably also drug-conjugates formed in upstream hepatocytes to downstream hepatocytes. This likely helps to prevent saturation of further detoxification processes (e.g., biliary excretion) and subsequent hepatocyte toxic injury in the upstream hepatocytes. In close collaboration with Dr. M. Jirsa (Charles University, Prague), we subsequently demonstrated that the human Rotor syndrome, a benign hereditary conjugated hyperbilirubinemia, is a two-gene disorder, caused by impaired hepatocellular (re-)uptake of bilirubin glucuronide and other compounds owing to complete deficiencies of OATP1B1 and OATP1B3 (Van de Steeg et al, 2012). Since even partial OATP1B1 deficiencies cause life-threatening drug hypersensitivities in humans, the newly identified OATP1B1 and OATP1B3 null mutations likely confer substantial drug toxicity risks. Slco1a/1b-/- mice not only showed decreased hepatic uptake and increased systemic exposure of the anionic drug methotrexate, but also of the bulky hydrophobic anticancer drug paclitaxel. Humanized OATP1B1 and OATP1B3 could mostly rescue these phenotypes, suggesting a similar functional importance of these proteins in humans (Van de Steeg et al, 2013). Some Oatp1a/1b proteins are also expressed in the small intestine and thought to contribute to the intestinal uptake of orally administered drugs. However, despite extensive efforts, we have so far been unable to demonstrate any effect of the Oatp1a/1b knockout on the intestinal uptake of methotrexate, fexofenadine, or pravastatin (Van de Steeg et al, 2010; Iusuf et al, 2013). In conclusion, variation in OATP1A/1B activity due to genetic variation and pharmacological inhibition, or differences in tumor-specific expression levels might affect plasma, tissue, and tumor levels of these drugs in patients, and hence their therapeutic efficacy. The developed mouse models will provide excellent tools to study such questions.