p62/SQSTM1/A170 (hereafter referred to as p62) is a stress-inducible intracellular protein known to regulate various signal transduction pathways involved in cell survival and cell death. Comprehensive analysis of LC3 (an autophagosome localizing protein)-binding proteins resulted in the recognition of autophagy and p62. While autophagy modulates the level of p62 protein, p62 can suppress autophagy via activation of mTORC1. Moreover, growing lines of evidence point to the important role of p62 in directing ubiquitinated cargos toward autophagy as well as compaction of those cargos. Furthermore, this protein functions as a signaling hub for various signal transduction pathways, such as NF-κB signaling, apoptosis, and Nrf2 activation, whose dysregulation is associated with Paget disease of bone and tumorigenesis. In this review, we discuss the pathophysiological significance of p62 and its role in autophagy.