Bilirubin, a major end product of heme breakdown, is an important constituent of 
bile, responsible for its characteristic colour. Over recent decades, our 
understanding of bilirubin metabolism has expanded along with the processes of 
elimination of other endogenous and exogenous anionic substrates, mediated by 
the action of multiple transport systems at the sinusoidal and canalicular 
membrane of hepatocytes. Several inherited disorders characterised by impaired 
bilirubin conjugation (Crigler-Najjar syndrome type I and type II, Gilbert 
syndrome) or transport (Dubin-Johnson and Rotor syndrome) result in various 
degrees of hyperbilirubinemia of either the predominantly unconjugated or 
predominantly conjugated type. Moreover, disrupted regulation of hepatobiliary 
transport systems can explain jaundice in many acquired liver disorders. In this 
review, we discuss the recent data on liver bilirubin handling based on the 
discovery of the molecular basis of Rotor syndrome. The data show that a 
substantial fraction of bilirubin conjugates is primarily secreted by MRP3 at 
the sinusoidal membrane into the blood, from where they are subsequently 
reuptaken by sinusoidal membrane-bound organic anion transporting polypeptides 
OATP1B1 and OATP1B3. OATP1B proteins are also responsible for liver clearance of 
bilirubin conjugated in splanchnic organs, such as the intestine and kidney, and 
for a number of endogenous compounds, xenobiotics and drugs. Absence of one or 
both OATP1B proteins thus may have serious impact on toxicity of commonly used 
drugs cleared by this system such as statins, sartans, methotrexate or 
rifampicin. The liver-blood cycling of conjugated bilirubin is impaired in 
cholestatic and parenchymal liver diseases and this impairment most likely 
contributes to jaundice accompanying these disorders.