Kidney disease not only alters the renal elimination but also the non-renal disposition of drugs that are metabolized by the liver. Indeed, modifications in the expression and activity of intestinal and hepatic drug metabolism enzymes and uptake and efflux transporters have been reported. Accumulated uremic toxins, inflammatory cytokines, and parathyroid hormones may modulate these proteins either directly or by inhibiting gene expression. This can lead to important unintended variations in exposure and response when drugs are administered without dose adjustment for reduced renal function. This review summarizes our current understanding of non-renal clearance in circumstances of chronic and acute renal failure with experimental but also clinical studies. It also evaluates the clinical impact on drug disposition. Predicting the extent of the drug disposition modification is difficult first because of the complex interplay between metabolic enzymes and transport proteins but also because of the differential effects in the different organs (liver, intestines). Recommendations of the US FDA are presented as they may be potentially helpful tools to predict these modifications when no specific pharmacokinetic studies are available.