The NLRP3 inflammasome is a cytosolic complex that activates Caspase-1, leading to maturation of interleukin-1β (IL-1β) and IL-18 and induction of proinflammatory cell death in sentinel cells of the innate immune system. Diverse stimuli have been shown to activate the NLRP3 inflammasome during infection and metabolic diseases, implicating the pathway in triggering both adaptive and maladaptive inflammation in various clinically important settings. Here I discuss the emerging model that signals associated with mitochondrial destabilization may critically activate the NLRP3 inflammasome. Together with studies indicating an important role for Ca²⁺ signaling, these findings suggest that many stimuli engage Ca²⁺ signaling as an intermediate step to trigger mitochondrial destabilization, generating the mitochondrion-associated ligands that activate the NLRP3 inflammasome.