G protein-coupled receptors (GPCRs) are key mediators of cellular signaling, participating in various physiological and pathological processes. Emerging evidence reveals that GPCRs can form functional heterodimers, wherein two distinct receptor subtypes interact mutually to generate unique signaling complexes. GPCR heterodimers play a crucial role in modulating cellular responses and are involved in biased signaling, a phenomenon where receptor activation preferentially triggers specific intracellular pathways (e.g., G protein vs. β-arrestin pathways). In this review, we will explore the molecular mechanisms underlying GPCR heterodimerization and the modulation of biased signaling in heterodimers. We first discuss the assembly and activation mechanisms based on heterodimerization in Class C GPCRs. Furthermore, we explore the impact of receptor dimerization on downstream biased signaling and the physiological relevance of these heterodimers. Next, we also summarize three criteria and essential technologies for identifying potential heterodimers. Lastly, we address the challenges and future directions in the study of GPCR heterodimers, particularly for drug discovery, highlighting their potential in designing novel therapeutics with enhanced specificity and reduced side effects.