Melanoma is a devastating form of skin cancer in humans that is rising in incidence. Animal models of melanoma continue to be instrumental for understanding the disease and for developing and testing therapies. A novel line of melanoma-bearing mice developed at the National Institute of Neurological Disorders and Stroke is monitored and cared for by the Animal Health Care Section. Although these mice develop heavy tumor burdens, they show few signs of pain or distress and seem to have high levels of physiologic fitness. The author discusses the monitoring and care of these mice, advocating early flagging and frequent monitoring of melanoma-bearing mice. In the care of melanoma-bearing mice, an emphasis should be placed on evaluating the whole animal and considering new endpoints rather than relying on historically accepted guidelines for maximum tumor size and weight, which may be inappropriate for some mice.