Posttranslational modification of proteins by attachment of lipids touches almost all areas of cellular physiology. One of the major areas of interest in our lab are integral membrane enzymes that catalyze protein lipidation. The most widely prevalent form of protein lipidation is protein S-acylation or protein palmitoylation whereby membrane proximal cysteines are modified by fatty acids through a thioester linkage. Protein palmitoylation, owing to its inherent lability through the action of cellular thioesterases, offers a unique, potentially dynamic form of protein lipidation. There are 23 members of the DHHC family of integral membrane enzymes that catalyze protein palmitoylation and close to 1000 cellular proteins that are known to be palmitoylated. Yet, nothing was known till recently about their three-dimensional structure or detailed mechanism of action. Our work has led to the first high-resolution structure of two DHHC palmitoyltransferases and detailed insights into their chemical mechanism. They have enabled us to design engineered versions of human DHHC20 that open up the possibility of designing new tools for probing the physiology of DHHC enzymes. Chemical and pharmacological small molecule probes for DHHC enzymes are sorely lacking and our structural studies are also plausible starting points for such a small molecule probe discovery program.