Cancer is a life-threatening disease that has plagued humans for centuries. The vast majority of cancer-related mortality results from metastasis. Indeed, the invasive growth of metastatic cancer cells in vital organs causes fatal organ dysfunction, but metastasis-related deaths also result from cachexia, a debilitating wasting syndrome characterized by an involuntary loss of skeletal muscle mass and function. In fact, about 80% of metastatic cancer patients suffer from cachexia, which often renders them too weak to tolerate standard doses of anticancer therapies and makes them susceptible to death from cardiac and respiratory failure. The goals of this review are to highlight important findings that help explain how cancer-induced systemic changes drive the development of cachexia and to discuss unmet challenges and potential therapeutic strategies targeting cachexia to improve the quality of life and survival of cancer patients.