The number of technologies that enable high-throughput functional screening of G-protein-coupled receptors has expanded markedly over the past 5 years. Consequently, choosing the most appropriate technology can be a daunting task, particularly for Gi- or Gs-coupled receptors. The most common systems for cyclic AMP detection are reviewed, highlighting the practical and theoretical aspects that are important in their application to high-throughput screening. Current technologies can do the job, but it is likely that the future may require development of technologies that provide even greater biological information.