With a resurgence of interest in leucovorin calcium (LV), many questions about its role in cancer chemotherapy are being asked again. How does it modulate 5-fluorouracil (5-FU) therapy? Can it potentiate the cytotoxicity of 5-FU more in malignant than in normal cells? Does it rescue tumor cells from high-dose methotrexate (MTX) more than it does normal cells? How should LV rescue be individualized to maximize the therapeutic index? When can LV be administered orally, and how can LV rescue be conducted at home? When is LV rescue necessary, and what toxicities occur when it is inadequate? Some answers to these questions are provided in this review.