This review focuses on recent progress of laboratory studies in the understanding of the molecular mechanisms of cancer cachexia that centers on the role of systemic activation of Toll-like receptor 4 (TLR4) by cancer-released Hsp70 and Hsp90 in the development and progression of muscle wasting, and the downstream signaling pathways that activate muscle protein degradation through the ubiquitin–proteasome and the autophagy–lysosome pathways in response to TLR4 activation. The gene discussed is TLR4; the disease is cancer.