Background: A drug designed for a specific target often interacts with multiple targets, either unintentionally or as part of its intended mechanism of action. This phenomenon has been called pharmacological pleiotropy or polypharmacology. There are key endogenous ligands such as ATP, GABA and glutamate, that act on various proteins in humans. Furthermore, several drugs act on multiple proteins without apparent structural similarity. G protein-coupled receptors (GPCR) and protein kinases are among the most important families of drug targets. The aim of this review analysis is to identify drugs with dual actions on GPCRs and kinases and clarify what is known about these actions. Approach: Data searches for ligands with affinity for both kinases and GPCRs were conducted in the Drugbank and Pharos databases. Physiochemical properties of selected compounds were identified using the rdMolDescriptors module from RDKit. A detailed literature search was conducted in search engines such as Google Scholar and Medline, to identify pleiotropic compounds with both GPCR and kinase affinity. Outcome: 34 compounds were identified to interact with proteins within both the kinase and GPCR protein families. Notable examples included the drugs loratadine, terfenadine, clozapine, thioridazine, aripiprazole, fluspirilene, sorafenib, dasatinib, and fasudil. Conclusions: Drug pleiotropy among GPCRs and kinases is a commonly occurring phenomenon. Structural factors that may contribute to pleiotropy include chemical similarity to endogenous ligands, lipophilicity, and planarity of chemical structure, which may guide the development of drugs with intentional multi-target effects. While pleiotropy presents challenges in ensuring specificity, it also creates opportunities for innovative therapeutic strategies if strategically applied.