Systemic fungal infections are a major threaten for immunocompromised patients. Beside the antimycotic spectrum, the pharmacokinetic properties of an antifungal drug are crucial for its clinical efficacy. Since patients with systemic mycoses frequently present with a significant co-morbidity, pharmacokinetics under special conditions such as renal insufficiency, renal replacement therapy or impaired liver function have to be considered. Amphotericin B is eliminated unchanged by the liver and the kidney. Its plasma protein binding accounts for 95 to 99 percent. Conventional amphotericin B deoxycholate has a remarkable infusion related and renal toxicity. Therefore, lipid formulations have been developed. By now, three lipid formulations are therapeutically used: liposomal amphotericin B, amphotericin B colloidal dispersion and amphotericin B lipid complex. Striking differences in their plasma pharmacokinetics have been found. These differences can be attributed to the diverse disposition of the lipid moieties, while liberated amphotericin B displays a pharmacokinetic behavior which is independent from the lipid-formulation applied. The highest amphotericin B tissue concentrations have been found in the liver and in the spleen, followed by lung, kidney and heart. Concentrations in brain tissue are very low. Flucytosine has no relevant protein binding and is eliminated by glomerular filtration. Fluconazole, itraconazole, voriconazole, posaconazole and ravuconazole are triazoles, used for treatment of systemic fungal infections. Significant drug interactions have to be considered during therapy with triazoles, particularly in patients dependent on immunosuppression. These interactions are caused by the metabolism of triazoles in the liver where the cytochrome P450 (CYP) system is involved at a different extend as well as by their mechanisms of action. Triazoles display a favorable tissue distribution with high penetration into the central nervous system. Echinocandins such as caspofungin and micafungin are rapidly taken up by peripheral tissues, particularly by the liver. In the first 24 hours this uptake appears to be the main route of elimination from plasma. Enzymatic degradation takes place, but is independent of CYP. Thus, drug interactions are a minor problem during echinocandin treatment. The highest tissue levels of caspofungin and micafungin have been measured in the liver. Moderate concentrations are achieved in lung, spleen and kidney. Penetration into the brain is relatively poor.