GPR151 (G protein-coupled receptor 151) is an orphan class A G protein-coupled receptor predominantly expressed in the brain, particularly in the habenula, a region linked to aversive states, pain processing, and reward-related behaviors. Its endogenous ligand remains unidentified, but GPR151 is thought to modulate synaptic transmission and neuronal signaling through interactions with G proteins. Research highlights its potential role in neuropsychiatric disorders, including depression, anxiety, and addiction, as well as neuropathic pain. Antibodies targeting GPR151 are critical tools for investigating its expression patterns, cellular localization, and functional mechanisms. They enable techniques like immunohistochemistry, Western blotting, and flow cytometry to visualize receptor distribution in tissues or validate knockout models. Despite its therapeutic potential, challenges persist in characterizing GPR151 due to its low abundance, structural similarity to other GPCRs, and species-specific expression variations. Recent studies using GPR151 antibodies have revealed its involvement in regulating neurotransmitter release and synaptic plasticity, with knockout mice displaying altered responses to stress and addictive substances. However, inconsistencies in antibody specificity across studies underscore the need for rigorous validation. Developing high-affinity, selective antibodies remains pivotal for unraveling GPR151’s pathophysiology and exploring its viability as a drug target for neurological and mood disorders.