Prophylaxis against fungal infections is an important aspect of caring for immunocompromised individuals. Despite advances in non-culture based diagnostics and antifungal therapies, our ability to diagnose and treat invasive fungal infections remains challenging. Thus, prophylaxis remains the best strategy against morbidity and mortality from invasive fungal infection. Prophylaxis regimens are based on patient risk, which varies by underlying disease state and clinical history. Both pharmacologic and non-pharmacologic interventions are critical in reducing risk of invasive fungal infection among immunocompromised hosts. When choosing a pharmacologic prophylaxis strategy, both efficacy and toxicity are key considerations. Clinical trials and expert guidelines are available to advise clinicians on appropriate prophylaxis regimens for at-risk individuals.