G protein-coupled receptors (GPCRs) are privileged entry points for extracellular signals that are transmitted through the plasma membrane into the cell. GPCRs are highly druggable and are targeted by approximately 30% of the currently marketed drugs. They are involved in virtually any biological process and are potential therapeutic targets for many diseases such as cancer and metabolic diseases. Here, I will report on how atypical orphan GPCRs like GPR50 can function in a ligand-independent manner, either in macromolecular signaling complexes with other membrane receptors or through regulated proteolytic cleavage and nuclear translocation. This is relevant in cancer and obesity development. In the second part I will talk about the next-generation molecules to boost the activity of the GLP-1 receptor in the context of type 2 diabetes and obesity.