G protein-coupled receptors (GPCRs) constitute several membrane proteins that are turned on by hormones and neurotransmitters to trigger cellular signaling pathways. GPCRs have been targeted in the development of several drugs but the therapeutic potential of these proteins remains underutilized. Most drugs to date have targeted the class A, or the rhodopsin family of GPCRs, but recently the Class B, i.e., the secretin family of G protein receptors has been targeted for the treatment of metabolic diseases such as diabetes mellitus. Class B G protein-coupled receptors (GPCRs) have also been targeted for managing several clinical conditions such as diabetes mellitus, bone disorders, malignancies, neurodegeneration, cardiovascular diseases, neuropsychiatric disorders, etc. In this article, we review the medicinal chemistry and potential clinical role of targeting GPCRs with a special emphasis on cardiovascular pharmacology.