Fundamental to the successful implementation of antifungal compounds in neutropenic patients is the appropriate design of comparative clinical trials investigating their safety and efficacy. The key elements of comparative clinical trial design include issues of enrollment, stratification, randomization, blinding, administration of study drugs, monitoring of drug toxicity, definitions, and key statistical elements of end points, sample size, and tools for data analysis. The initial selection of compounds and the timing of initiation of antifungal therapy in comparative clinical trials are predicated to a large degree on the in vitro and in vivo activities, plasma pharmacokinetics, profiles of safety and toxicity of the study drugs. Phase I and II studies have a critical role in designing comparative clinical trials of antifungal therapy by providing data on safety, tolerance, and plasma pharmacokinetics of the investigational agent. As new antifungal agents are developed in response to the challenge of invasive fungal infections in immunocompromised patients with cancer, thoughtfully designed and carefully implemented clinical trials will be essential in determining the future utility of these promising compounds.