G protein-coupled receptors (GPCRs) form the most extensive family of membrane receptors and play a crucial role in converting extracellular signals into various intracellular responses. Conventional GPCR pharmacology has predominantly depended on orthosteric agonists and antagonists; however, recent developments have demonstrated that GPCR signaling is significantly more intricate, involving dynamic conformational ensembles governed by allosteric modulation and biased agonism. Allosteric modulators attach to places other than the endogenous ligand-binding pocket and change how the receptor works by boosting, lowering, or changing the direction of signaling without fully activating or blocking the receptor. This mechanism provides significant therapeutic benefits, including enhanced receptor subtype selectivity, ceiling effects that improve safety, and the maintenance of physiological signaling. Simultaneously, biased agonism (functional selectivity) has arisen as a revolutionary concept, illustrating that ligands can selectively activate particular downstream pathways, including G protein- or β-arrestin-mediated signaling. Biased ligands offer a potent approach for precision pharmacology by selectively activating therapeutically advantageous pathways while circumventing those associated with adverse effects. Recent advances in structure and computation, such as cryo-electron microscopy, molecular dynamics simulations, and machine learning, have shed light on the molecular basis of allosteric regulation and signaling bias. These advances have revealed important microswitches, residue networks, and water-mediated interactions that control pathway selectivity. This chapter thoroughly analyzes the concepts, molecular mechanisms, pharmacological characterization, and therapeutic prospects of GPCR allosteric modulators, biased ligands, and biased allosteric modulators. It talks about recent advances in structural biology, drug discovery, and translational applications for neurological, cardiovascular, metabolic, and oncological diseases. It also talks about current problems like bias quantification, probe dependence, and in vitro-in vivo translation. These insights collectively highlight the potential of next-generation GPCR therapeutics founded on precise modulation of receptor signaling.