Abstract: Multipass membrane proteins serve as crucial channels connecting the intracellular and extracellular environments of cells, transmitting various signals and regulating cellular responses to external stimuli. Many human diseases are closely associated with abnormalities in the function of multipass membrane proteins, making them ideal targets for drug intervention. In comparison to existing treatment approaches dominated by small molecules and peptides, antibody-based drugs offer advantages such as high specificity, providing a new avenue for regulating the function of multipass membrane proteins. However, the development of antibody drugs targeting multipass membrane proteins faces numerous challenges. The complexity of their structure presents unique obstacles, including epitope accessibility, difficulties in protein expression, and dynamic protein conformations. Innovative strategies are needed to drive corresponding antibody drug development. This discussion explores the challenges posed by the complex structures of multipass membrane proteins for antibody drug development and introduces new approaches developed in recent years to overcome these obstacles. The review systematically summarizes current antibody drug research targeting multipass membrane proteins. As this field progresses, insights gained from antibody drug discovery targeting multipass membrane proteins not only contribute to improving therapeutic interventions but also hold significant value for advancing broader drug discovery innovations.