Though interferons (IFNs) were once heralded as panaceas to numerous diseases, how cells decode varying IFN stimuli and subsequently produce (in)appropriate signaling remain unclear. Our labs recently engineered novel erythropoietin receptor-IFN chimeric receptors, and we highlight their utility in two cases uncovering differential genetic determinants of type I (IFN-α/β) and type III (IFN-λ) IFN signaling. These and other types of synthetic (cytokine) receptors could be expanded to real-time signaling dynamics and studies.