The G protein-coupled receptor (GPCR) superfamily of integral proteins is the largest family of signal transducers, comprised of ∼1000 members. Considering their prevalence and functional importance, it’s not surprising that ∼60% of drugs target GPCRs. Regardless, there exists a subset of the GPCR superfamily that is largely uncharacterized and poorly understood; specifically, more than 140 GPCRs have unknown endogenous ligands—the so-called orphan GPCRs. Orphan GPCRs offer tremendous promise, as they may provide novel therapeutic targets that may be more selective than currently known receptors, resulting in the potential reduction in side effects. In addition, they may provide access to signal transduction pathways currently unknown, allowing for new strategies in drug design. Regardless, orphan GPCRs are an important area of inquiry, as they represent a large gap in our understanding of signal transduction at the cellular level. Here, we focus on the therapeutic potential of two recently deorphanized GPCRs: GPR35/CXCR8 and GPR55. First, GPR35/CXCR8 has been observed in numerous tissues/organ systems, including the gastrointestinal tract, liver, immune system, central nervous system, and cardiovascular system. Not surprisingly, GPR35/CXCR8 has been implicated in numerous pathologies involving these tissues/systems. While several endogenous ligands have been identified, GPR35/CXCR8 has recently been observed to bind the chemokine CXCL17. Second, GPR55 has been observed to be expressed in the central nervous system, adrenal glands, gastrointestinal tract, lung, liver, uterus, bladder, kidney, and bone, as well as, other tissues/organ systems. Likewise, it is not surprising that GPR55 has been implicated in pathologies involving these tissues/systems. GPR55 was initially deorphanized as a cannabinoid receptor and this receptor does bind many cannabinoid compounds. However, the GPR55 endogenous ligand has been found to be a non-cannabinoid, lysophophatidylinositol (LPI) and subsequent high throughput assays have identified other GPR55 ligands that are not cannabinoids and do not bind to either the cannabinoid CB1 and CB2 receptors. Here, we review reports that suggest that GPR35/CXCR8 and GPR55 may be promising therapeutic targets, with diverse physiological roles.