p62/SQSTM1 is a multifunctional protein involved in the autophagic clearance and degradation of ubiquitinated protein aggregates and damaged organelles. p62 is also involved in activation of several signaling pathways, including those that regulate transcription factors NRF2 and NF-κB. It has been observed that p62-containing aggregates accumulate in human hepatocellular carcinoma (HCC) and nonalcoholic steatohepatitis (NASH), a premalignant condition associated with obesity and hypernutrition. We found that p62 also accumulates in the majority of pancreatic ductal adenocarcinomas (PDAC) and in chronic pancreatitis, an inflammatory disease that greatly enhances PDAC risk. In both HCC and PDAC, p62 plays a critical oncogenic function, but counter to previous expectations, this function is not mediated through the activation of NF-κB. Instead, p62 accumulation is associated with enhanced stemness and activation of quiescent early dysplastic lesions. The mechanisms through which p62 promotes malignancy and tumor establishment will be discussed.