In the more than 30 years since hydroxyurea was first evaluated clinically, a number of diverse and unique applications have been identified for its use. Some of these applications were apparent to investigators almost from the beginning, while others are still evolving 3 decades later as a result of ongoing research. An overview of clinical experience with hydroxyurea provides an historical perspective on a period encompassing virtually the entire era in which anticancer chemotherapy has been a recognized discipline. The critical role of the ribonucleotide reductase reaction in the regulation of DNA synthesis makes this enzyme a particularly important target site for antineoplastic therapy. The sustained interest in hydroxyurea, however, has been the result of careful clinical observations as well as basic laboratory studies, which support current attempts to identify additional uses for the drug. This overview describes the clinical development of hydroxyurea, discusses current indications, and briefly describes areas of ongoing research that may expand the clinical indications for hydroxyurea.