Amyotrophic lateral sclerosis and frontotemporal lobar degeneration are multifaceted diseases with genotypic, pathological and clinical overlap. One such overlap is the presence of SQSTM1/p62 mutations. While traditionally mutations manifesting in the ubiquitin-associated domain of p62 were associated with Paget's disease of bone, mutations affecting all functional domains of p62 have now been identified in amyotrophic lateral sclerosis and frontotemporal lobar degeneration patients. p62 is a multifunctional protein that facilitates protein degradation through autophagy and the ubiquitin-proteasome system, and also regulates cell survival via the Nrf2 antioxidant response pathway, the nuclear factor-kappa B signaling pathway and apoptosis. Dysfunction in these signaling and protein degradation pathways have been observed in amyotrophic lateral sclerosis and frontotemporal lobar degeneration, and mutations that affect the role of p62 in these pathways may contribute to disease pathogenesis. In this review we discuss the role of p62 in these pathways, the effects of p62 mutations and the effect of mutations in the p62 modulator TANK-binding kinase 1, in relation to amyotrophic lateral sclerosis-frontotemporal lobar degeneration pathogenesis.