Inflammasomes are multi-protein complexes that regulate the innate immune response by facilitating the release of inflammatory cytokines in response to pathogen exposure or cellular damage. Pro-inflammatory inflammasome signaling is vital to host defense and helps initiate the process of tissue repair following an insult to the host, but can be injurious, when excessive or chronic. As such, inflammasome activity is tightly regulated. Here we discuss one critical mechanism of inflammasome regulation, ubiquitination, that functions as a universal modulator of protein stability and trafficking. Recent studies have provided important insights into the regulation of inflammasome activation by protein ubiquitination. We review the molecular regulation of inflammasome function, specifically, as it relates to ubiquitination, and discuss the implications for the development of therapeutics to specifically target aberrant inflammasome signaling.