Organelles are critical structures in mediating the assembly and activation of inflammasomes in mammalian cells, resulting in inflammation and cell death. Assembly of inflammasomes can occur at the mitochondria, endoplasmic reticulum, nucleus, trans-Golgi network, or pathogen surface, facilitated by the overarching architecture of the cytoskeleton. NLRP3 and Pyrin inflammasome sensors may form smaller speckles and converge on a single larger speck at the microtubule-organizing center (MTOC). This signaling hub activates multiple mammalian inflammatory and apoptotic caspases, cytokine substrates, the pore-forming protein gasdermin D, and the plasma membrane rupture protein ninjurin-1 (NINJ1), allowing pyroptosis, cellular disintegration, and inflammation to ensue. In this review, we highlight the role of mammalian cell types and organellar architectures in executing inflammasome responses.