1. The liver is ideally suited for the efficient uptake of drugs from sinusoidal blood. For most drugs, uptake into hepatocytes across the basolateral membrane occurs via passive diffusion, with minimal reliance on carrier-mediated transport systems. Often, this passive diffusion is so efficient that uptake is rate-limited by the delivery of the drug to the liver (i.e. blood flow) rather than membrane transport per se. 2. For highly polar molecules, passive diffusion no longer represents an efficient mode of hepatocellular uptake and there is an increased reliance on carrier-mediated transport systems. For these compounds, membrane transport may dictate the overall efficiency of hepatic elimination. 3. Drug metabolites, particularly conjugated metabolites, such as sulphates and glucuronides, are invariably more polar than their precursors and are more likely to experience hepatocyte membranes as diffusional barriers. In the presence of such a barrier, the hepatocellular disposal of a locally formed metabolite will depend critically on the presence and activity of carrier-mediated transport systems for sinusoidal efflux and biliary excretion. Transporters of current interest include P-glycoproteins, which are responsible for the biliary excretion of a range of organic cations, and the canalicular multispecific organic anion transporter. 4. Intracellular trapping of hepatically formed metabolites, secondary to low membrane permeability, is clinically important as many metabolites are potentially hepatotoxic and/or capable of interfering with the hepatic transport of endogenous compounds or other drugs and metabolites. In addition, if the metabolite is unstable, intracellular accumulation can lead to the regeneration of the precursor and 'futile cycling' within hepatocytes. 5. An increased understanding of the factors influencing the intracellular concentration of drugs and hepatically formed metabolites in the liver will improve our ability to specifically treat liver disorders, such as hepatocellular carcinoma and malaria, and minimize the risk of hepatotoxicity from drugs and other xenobiotics.