Fungal infections continue to emerge as an important cause of infectious disease and mortality in humans. Amphotericin B deoxycholate (ABD), was the first antifungal that was discovered, and it was released in 1958, and flucytosine, which was developed later and is effective against Candida and Cryptococcus, was introduced in 1978. The discovery of first-generation azoles (fluconazole and itraconazole) in the 1990s has created a new step in the treatment of fungi. In the years that followed, with the development of lipid formulations of amphotericin B, the introduction of second-generation azoles, and the release of the most recently developed class, echinocandins, the foundations of today’s existing antifungal classes were laid. This article is aimed to review the mechanism of action, side effects and clinical use indications of the main antifungal drugs used in the treatment of systemic fungal infections.