This Special Issue aims to collect new reports and insights from computational and experimental researchers on specific problems of great significance in GPCR signaling. The fundamental concept of “functional selectivity” or “ligand bias”, e.g., the molecular mechanisms for selectivity for different pathways and the design of new drugs targeting these pathways, is of enormous interest in molecular pharmacology, cell physiology, and drug development. Contributions to this issue, both in the form of original research or review articles, may cover all aspects of GPCR mechanism and drug design and multidisciplinary studies are particularly welcome.