The nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome has emerged as a key mediator of pathological inflammation in many diseases and is an exciting drug target. Here, we review the molecular basis of NLRP3 inhibition by drug-like small molecules under development as novel therapeutics. We also summarize recent strategies to block pyroptosis as a novel approach to suppress chronic inflammation. Major recent developments in this area include the elucidation of mechanisms of action (MoAs) by which small molecules block NLRP3 inflammasome assembly and gasdermin D (GSDMD)-induced pyroptosis. We also discuss the status of clinical trials using agents that block specific components of the NLRP3 pathway, including their potential clinical applications for the treatment of many diseases.