More and more it is being appreciated that not all GPCRs are the same, sub-populations of GPCRs exist within a cell and function differently than others. The question is, how does one regulate a given sub-population? One way is through the addition of post-translational modifications to G-protein coupled receptors (GPCR). This process has long been known to occur and play a role in trafficking, pharmacology and ultimately function. This chapter will focus on one particular modification, that of S-palmitoylation, and its impact on GPCR function. We will discuss the history of this modification on these receptors and the connection with disease. We will highlight several examples from the literature of where palmitoylation impacts GPCR function.