This podcast episode explores orphan receptors - cellular proteins whose natural activating molecules (ligands) remain unknown. The discussion covers how scientists work to "deorphanize" these receptors using various techniques like high-throughput screening and structure-based design. The episode highlights specific examples like GPR17 and GPR35 receptors, and discusses how understanding these mysterious receptors could lead to breakthrough treatments for various diseases. The conversation also delves into unexpected discoveries about receptor functions, including potential connections between gut bacteria and human health through orphan receptors.