Section 2 describes the domain structure of p62, its post-translational modifications, and interacting proteins. In Section 3, we discuss the role of p62 as a receptor in autophagy and its regulation, and in Section 4, its involvement in signaling pathways, namely inflammasomes (Section 4.1), Nrf2 (Section 4.2), mTOR (Section 4.3), and NF-κB (Section 4.4). In Section 5, we address the mechanisms underlying deregulated expression in cancer and the consequences with HCCs as an example. This evidence concerns the gene NFE2L2 and cancer.