NLRP3 is a key regulator of the innate immune system involved in sensing a variety of pathogen and danger signals. Priming and activation of NLRP3 leads to the release and maturation of pro-inflammatory cytokines, as well as gasdermin D-mediated cell death. Inhibition of dysregulated NLRP3 activity has been associated with promising therapeutic opportunities for a variety of systemic and neurological diseases including atherosclerosis and Parkinson's disease. Herein, we discuss how a high-throughput screen (HTS) allowed us to discover new chemical scaffolds that specifically bind to NLRP3 and inhibit its function in a selective manner. We also describe how an enantiomer of HTS hit 5, compound 11, demonstrated in vivo inhibition of NLRP3.