Invasive fungal infections continue to be a significant cause of morbidity and mortality among at-risk patients. Over the last decade, the epidemiology of invasive mycoses has been defined by increasing rates of infection caused by azole-resistant yeast (Candida glabrata, Candida krusei), Aspergillus, and in some centers, non-Aspergillus moulds, such as Fusarium species, Scedosporium species, and Mucorales. Early and appropriate antifungal therapy is crucial for a favorable clinical outcome. When selecting antifungal therapy—especially during the initial acute phases of treatment—spectrum of activity and pharmacokinetic characteristics are key treatment considerations. Important pharmacokinetic considerations for selecting antifungal therapy in the treatment of invasive fungal infections include drug–drug interactions and variability in adsorption that may limit efficacy during the early phase of treatment, poor oral availability, and variable tissue distribution. A patient's underlying condition and pharmacogenetics also may affect the pharmacokinetics of antifungal drugs, resulting in interpatient pharmacokinetic differences.