Despite greater knowledge and possibilities in pharmacotherapy, fungal infections remain a challenge for clinicians. As the population of immunocompromised patients and those treated for their hematologic ailments increases, the number of fungal infections grows too. This is why there is still a quest for new antifungal drugs as well as for optimization of pharmacotherapy with already registered pharmaceutics. Voriconazole and posaconazole are broad-spectrum, new generation, triazole antifungal agents. The drugs are used in the pharmacotherapy of invasive aspergillosis, Candida and Fusarium infections. Voriconazole is also used in infections caused by Scedosporium . Posaconazole is used in the treatment of coccidioidomycosis and chromoblastomycosis. Besides some similarities, the two mentioned drugs also show differences in therapeutic indications, pharmacokinetics (mainly absorption and metabolism), frequency and severity of adverse drug reactions, drug–drug interactions and dosage. As both of the drugs are used in the treatment of invasive fungal infections in adults and children, detailed knowledge of the clinical pharmacology of antifungal agents is the main factor in pharmacotherapy optimization in treatment of fungal infections. The goal of the article is to present and compare the clinical pharmacology of voriconazole and posaconazole as well as to point out the indications and contraindications of using the drugs, determine factors influencing their pharmacotherapy, and provide information that might be helpful in the treatment of fungal infections.