G protein-coupled receptors (GPCRs) represent one of the largest and most diverse families of membrane receptors, playing a pivotal role in regulating a wide array of physiological processes. Despite their importance in human health and disease, the complexity of GPCR signalling and the challenge of targeting their dynamic functions for therapeutic intervention require advanced approaches to drug discovery. Systems biology offers a powerful framework for addressing these challenges by integrating multiple biological data layers, such as genomics, transcriptomics, proteomics, and metabolomics. This chapter explores the applications of systems biology in GPCR drug discovery, with a focus on target identification, drug repurposing, biased agonists, and personalized therapy. Through computational modelling, multi-omics profiling, and network pharmacology, systems biology provides critical insights into receptor function, cellular signalling networks, and drug interactions, enabling the development of more precise and effective GPCR-targeted therapies. Additionally, the integration of systems biology with experimental techniques offers new opportunities to understand and manipulate GPCR signalling, paving the way for novel drug discoveries in various disease contexts, including cancer, neurodegeneration, and cardiovascular diseases.