Inflammasomes are multi-protein complexes critical to the innate immune response. Among the four types of inflammasomes, the best studied one is the NLRP3 inflammasome. Abnormal NLRP3 activation is associated with various autoinflammatory and autoimmune diseases, such as type 2 diabetes, atherosclerosis, and Alzheimer’s disease. While the molecular mechanisms linking NLRP3 activation to disease remain poorly understood, researchers are gaining many vital clues. The NLRP3 inflammasome has been reported to consist of three main components: a sensor (NLRP3), an adaptor (ASC/PYCARD), and an effector (caspase-1), each of which is controlled by multiple post-translational modifications (PTMs). The ubiquitin system controls the NLRP3 sensor’s stability and priming. while phosphorylation controls NLRP3 self-association and interacting networks. For the ASC adaptor, ubiquitination control oligomerization, while phosphorylation regulates ASC localization and assembly. Less is known about how PTMs control the caspase-1 effector, although ubiquitination and phosphorylation are reported to play important roles. Targeting enzymes that write, read, and erase these various PTMs could be one way to treat diseases associated with the NLRP3 inflammasome. Further studies are needed to understand the mechanisms of PTM regulation and how to manipulate it to target the origins of various inflammatory diseases.