Today, invasive candidal infections are much less of a problem in patients undergoing hematopoietic stem cell transplantation (HSCT) than they were in the 1980s, principally because of widespread application of effective antifungal prophylaxis strategies. Two randomized, placebo-controlled studies performed in the early 1990s were instrumental in demonstrating the protective effects of fluconazole. Although both studies showed that candidiasis is prevented by fluconazole prophylaxis, controversies regarding optimal administration guidelines and the impact on survival after HSCT have persisted over the last decade. Details of how these trials were done, including the patients enrolled and end points evaluated, explain many of the different findings and controversies. An understanding of design issues can help explain current controversies and can assist in development of future prophylaxis studies.