Since the 1970s, the death rate from Candida infection has risen in conjunction with increasing numbers of patients at risk for serious fungal infections, such as those immunocompromised because of tissue or organ transplantation, chemotherapy, acquired immunodeficiency syndrome, or advanced age. Candidal infections are not only prevalent but also associated with considerable mortality and morbidity. In 2005, the overall mortality rate was 44% within 30 days of the first blood culture positive for any Candida species. Given the substantial morbidity and mortality, clinicians must include fungal infection in the differential diagnosis for at-risk patients, and they must quickly select appropriate antifungal therapy for those with identified infection. However, clinicians cannot use the minimum inhibitory concentration to select antifungal therapy in the same way they use it to treat bacterial infections. The relationship between in vitro susceptibility and clinical effect is not as direct with antifungals as it is with antibiotics. As long as Candida species continue to be the major causes of fungal infections, improving outcomes remains an important therapeutic goal. A key element is preventing and managing drug resistance. Further study of treatment duration, dosage, intermittent-versus-continuous administration schedules, and other treatment options are needed to determine their effect on resistance. Therapy that combines agents with complementary mechanisms of action may increase potency and broaden the spectrum of antifungal efficacy while decreasing the number of resistant organisms.