Opioids, both endogenous and exogenous, have a strong influence on the renal function through different mechanisms, producing changes in the renal excretion of water and sodium. Several studies have demonstrated that opioids influence renal function, according to the agonist profile used. Mu, kappa, and delta agonists produce different renal effects, although the mechanisms remain unclear. Experimental data have given the input for a possible therapeutic role of kappa agonists for some specific conditions, for example, in treating water retention or hyponatremia occurring in patients who have hepatic cirrhosis with ascites. On the other hand, changes in renal function might strongly condition the use of opioids in the clinical setting, and the knowledge of the relationship between opioids and renal function is mandatory for a tailored approach to accommodate the individual responses in terms of pain intensity, tolerance, and adverse effects experienced by these groups of patients. The influence of renal function when using different opioids in the clinical setting is reviewed, as well as problems related to transplantation, renal damage induced by opioid addiction, and problems related to the use of opioid antagonists in such conditions.Endogenous opioids exert physiologic effects on renal function, and the use of opioids may have an influence on renal activity. Renal impairment has a serious impact on the clearance of most opioids used in the clinical setting. Biochemical and clinical monitoring is mandatory to prevent serious complications.