G protein-coupled receptors (GPCRs) are essential modulators of cellular signaling and constitute the most extensive class of drug targets in humans. Traditionally regarded as regulators of physiological equilibrium, increasing evidence indicates that prolonged, excessive, or dysregulated activation of GPCRs can paradoxically lead to cellular toxicity. This chapter offers a thorough examination of GPCR-mediated cellular toxicity, incorporating molecular, cellular, and translational viewpoints. The primary processes examined encompass prolonged β-arrestin signaling, calcium overload, mitochondrial dysfunction, endoplasmic reticulum stress, oxidative stress, skewed agonism, constitutive receptor activation, and interaction with death receptor pathways. The chapter additionally elucidates how endogenous ligands generated during stress and inflammation, along with commonly utilized GPCR-targeting pharmaceuticals, can reveal hazardous signaling contingent upon dosage, duration, and hereditary predisposition. This work synthesizes concepts from disease biology, drug development, experimental techniques, and precision medicine, highlighting the dual nature of GPCR signaling and the need to comprehend dangerous signaling networks to enhance therapeutic safety and efficacy.