Innate immunity is the primary host defense against invading microorganisms. Pathogen recognition, mediated through an elaborate 'microbial sensing' system comprising the Toll-like and Nod-like receptor families results in the activation of caspase-1, which is a prerequisite for pathogen clearance. Tight regulation of caspase-1 is necessary to control the magnitude of the innate immune response and protect the organism from possible damaging effects such as sepsis. Recent findings from population studies and animal models of infectious diseases and sepsis have uncovered a role for full-length caspase-12 in blocking the inflammatory response initiated by caspase-1, thus predisposing the organism to severe sepsis and sepsis-related lethality. In this review, we re-examine the relationship among the Group I caspases, their known substrates and their proposed role in apoptosis. We further discuss their function in inflammation and bacterial clearance, with an emphasis on their regulatory mechanisms during the innate immune response.