Despite demonstrated efficiency in antibody generation, classical immunization strategies and subsequent hybridoma generation often face strong limitations when it comes to speed and poorly immunogenic membrane proteins with short extracellular domains. Indeed, even if a few antibodies can be obtained with repeated campaigns, only limited diversity and molecular characteristics are sometimes achieved, resulting in difficulties in selecting good candidates for pharmaceutical developments. Innovative approaches combining RNA immunization and single cell screening provide unique opportunities to dramatically speed up antibody discovery against such challenging targets. In the presentation, rapide obtention of large collections of antibodies with both molecular and function diversity on ‘classical’ targets as well as against a difficult GPCR and ion channel will be examplified using these strategies.