G protein-coupled receptors (GPCRs) remain one of the most therapeutically essential drug targets, accounting for a substantial proportion of approved medicines. Recent advances in GPCR-targeted drug discovery have been driven by innovative strategies, such as structure-based design, biased agonism, and allosteric modulation. Successful case studies highlight how these approaches translate into clinically effective therapies. Simultaneously, emerging technologies—including single-cell and spatial profiling, live-cell imaging, biosensors, and nanotechnology—have transformed the understanding of GPCR signaling dynamics in physiologically relevant contexts. Despite these advances, challenges related to receptor complexity, signaling bias, and translational predictability persist. Future progress will depend on integrating multidisciplinary technologies to enable more precise, safe, and personalized GPCR-based therapeutics.