The p62/Sequestosome 1 (p62, SQSTM1) protein is a scaffold protein that binds polyubiquitin chains and forms a cytoplasmic “sequestosome” where ubiquitinated, mis-fold, or non-functional proteins are stored for autophagic degradation. Tumor cells often utilize autophagy for survival in low nutrient and hypoxic conditions or in response to cancer treatments. Inhibition of p62 action may enhance chemotherapies by disrupting the pro-survival signaling cascades that work to maintain cell integrity and limit apoptosis. P62 functions in concert with tumor necrosis factor receptor associated factor 6 to mediate activation of nuclear factor kappa-B signaling pathway in response to upstream signals involving atypical protein kinase C. Over expression or dysregulation of p62 interactions can result in large cytoplasmic aggregates including those found in aggregation diseases affecting the brain and liver.