Inflammasomes are key signaling platforms that detect pathogenic microorganisms and sterile stressors, and activate the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. This review discusses the complex regulatory mechanisms that facilitate a balanced but effective inflammasome-mediated immune response, and highlights similarities to the apoptosome, another molecular signaling platform that monitors cellular health. Extracellular and intracellular mechanisms, including ion fluxes, free radicals, and autophagy, are discussed. The innate immune system recognizes foreign and self molecules, and inflammasomes are multimeric protein complexes consisting of an inflammasome sensor molecule, the adaptor protein ASC, and caspase 1. Inflammasome formation is triggered by various substances during infections, tissue damage, or metabolic imbalances. Once formed, inflammasomes activate caspase 1, which proteolytically activates IL-1β and IL-18, and induces pyroptosis, a rapid form of cell death. The discovery of pattern recognition receptors (PRRs) and their signaling pathways has enhanced understanding of how the immune system protects the host at a molecular level. Immune dysregulation contributes to diseases like atherosclerosis, type 2 diabetes, cancer, and neurodegenerative diseases. A balance between activation and inhibition of inflammation is essential for the immune system to remove danger without harming the host. The review presents an overview of inflammasome activation and regulation, discusses non-canonical processing of IL-1β, and compares inflammasome and apoptosome structures and regulation. Inflammasome sensor molecules detect a broad range of molecular signatures, triggering robust inflammatory responses via inflammatory caspases. However, not all NLR molecules form inflammasomes, and other NLR functions may be important. Some inflammasome sensor molecules require co-receptors for activation. NLRP1 binds directly to its ligand, muramyl dipeptide, and requires NOD2 for activation. NLRC4 requires co-receptors like NAIP for activation. NLRP3 is unique in requiring a two-checkpoint activation mechanism. NLRP3 activation is influenced by various activators, including crystalline material, peptide aggregates, and bacterial toxins. The activation of caspase 1 following recognition of live Gram-negative bacteria depends on inflammatory pro-caspase 11, leading to non-canonical NLRP3 inflammasome activation. Caspase 11 is involved in activating caspase 1 in response to bacteria. Caspase 8 can also cleave pro-IL-1β during immune responses. Inflammasome activation is regulated by cell-extrinsic factors, including positive and negative regulators. NLRP3 activation is regulated by transcriptional and post-translational mechanisms. The threshold of inflammasome activationInflammasomes are key signaling platforms that detect pathogenic microorganisms and sterile stressors, and activate the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. This review discusses the complex regulatory mechanisms that facilitate a balanced but effective inflammasome-mediated immune response, and highlights similarities to the apoptosome, another molecular signaling platform that monitors cellular health. Extracellular and intracellular mechanisms, including ion fluxes, free radicals, and autophagy, are discussed. The innate immune system recognizes foreign and self molecules, and inflammasomes are multimeric protein complexes consisting of an inflammasome sensor molecule, the adaptor protein ASC, and caspase 1. Inflammasome formation is triggered by various substances during infections, tissue damage, or metabolic imbalances. Once formed, inflammasomes activate caspase 1, which proteolytically activates IL-1β and IL-18, and induces pyroptosis, a rapid form of cell death. The discovery of pattern recognition receptors (PRRs) and their signaling pathways has enhanced understanding of how the immune system protects the host at a molecular level. Immune dysregulation contributes to diseases like atherosclerosis, type 2 diabetes, cancer, and neurodegenerative diseases. A balance between activation and inhibition of inflammation is essential for the immune system to remove danger without harming the host. The review presents an overview of inflammasome activation and regulation, discusses non-canonical processing of IL-1β, and compares inflammasome and apoptosome structures and regulation. Inflammasome sensor molecules detect a broad range of molecular signatures, triggering robust inflammatory responses via inflammatory caspases. However, not all NLR molecules form inflammasomes, and other NLR functions may be important. Some inflammasome sensor molecules require co-receptors for activation. NLRP1 binds directly to its ligand, muramyl dipeptide, and requires NOD2 for activation. NLRC4 requires co-receptors like NAIP for activation. NLRP3 is unique in requiring a two-checkpoint activation mechanism. NLRP3 activation is influenced by various activators, including crystalline material, peptide aggregates, and bacterial toxins. The activation of caspase 1 following recognition of live Gram-negative bacteria depends on inflammatory pro-caspase 11, leading to non-canonical NLRP3 inflammasome activation. Caspase 11 is involved in activating caspase 1 in response to bacteria. Caspase 8 can also cleave pro-IL-1β during immune responses. Inflammasome activation is regulated by cell-extrinsic factors, including positive and negative regulators. NLRP3 activation is regulated by transcriptional and post-translational mechanisms. The threshold of inflammasome activation