Caspases are cellular proteases that play essential roles in the regulation of programmed cell death, immunity and cell homeostasis via the targeting of their substrates. Caspase-1 is activated in response to danger and microbial signals via inflammasome assembly and has an important role during infection and inflammation. Despite extensive knowledge on the pathways leading to caspase-1 activation, less is known about the cellular proteins targeted by caspase-1 to promote inflammasome-mediated effector mechanisms, such as pyroptosis and pro-inflammatory cytokine release. Although initially identified as an apoptotic caspase, caspase-8 also participates in the regulation of inflammatory responses and cellular homeostasis. However, the caspase-8 substrates involved in these processes are largely unknown. In this study I investigated the roles of novel targets of caspase-1 and caspase-8 in inflammation and cell homeostasis. Caspase-1 was found to directly process ARFGAP2, an Arf1 GTPase-activating protein, and indirectly affect GNAI2, a heterotrimeric protein G subunit. Initial studies revealed these proteins may regulate caspase-1-dependent processes in cells. Caspase-8 was found to proteolytically process p62/Sequestosome-1, encoded by SQSTM1. p62 is a multifunctional scaffold protein involved in autophagy, immunity and oncogenesis. The stable N-terminal fragment, p62TRM (“trimmed”), was generated by caspase-8 during leucine starvation, TLR3 or TNF-receptor activation or bacterial infection. p62TRM regulated cellular homeostasis via the activation of the mechanistic target of rapamycin complex 1 (mTORC1) in response to leucine sensing, but was unable to perform autophagy-related functions. Notably, naturally occurring mutations in human p62 associated to neurodegenerative disease abrogated p62 processing into p62TRM, thus failing to regulate mTORC1 function and revealing a potential link between the mutations and the disease. These findings on the roles of caspase-8-dependent p62TRM generation further our understanding of caspase-mediated regulation of metabolism and p62-linked diseases. Future studies on caspase substrates will provide new insights into the roles of caspases in immunity and homeostasis.