PANoptosis, a unique new form of programmed cell death (PCD), is characterized by pyroptosis, apoptosis, and necroptosis, but it cannot be explained by pyroptosis, apoptosis or necroptosis alone. Assembly of the PANoptosome complex is a key feature of PANoptosis. To date, four kinds of PANoptosomes with distinct sensors and regulators have been defined, namely Z-DNA binding protein 1 (ZBP1) PANoptosome, absent in melanoma 2 (AIM2) PANoptosome, receptor-interacting protein kinase 1 (RIPK1) PANoptosome, and nucleotide-binding leucine-rich repeat-containing receptor 12 (NLRP12). Each PANoptosome contains three components: sensors for pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), adaptors as connected bridges, and catalytic effectors or executioners. Mechanistically, different PAMPs or DAMPs are recognized by the sensors in a context-dependent manner, which initiates PANoptosome assembly through adaptors, and ultimately engages synchronous activation of pyroptosis, apoptosis, and necroptosis via different catalytic effectors. Resultantly, PANoptosis is emerged as a prospective and promising therapeutic target for various diseases. This review covers the accumulating evidence about the roles and mechanisms of PANoptosis in innate immunity and discusses the attractive prospect of manipulating PANoptosis as a new treatment for diseases.