Cytokine and growth-factor ligands typically signal through homo- or hetero-dimeric cell surface receptors via Janus Kinase (JAK/TYK), or Receptor Tyrosine Kinase (RTK)-mediated trans-phosphorylation. However, the number of receptor dimer pairings occurring in nature is limited to those driven by natural ligands encoded within our genome. We have engineered synthethic cytokines (synthekines) that drive formation of cytokine receptor dimer pairings that are not formed by endogenous cytokines and that are not found in nature, and which activate distinct signaling programs. We show that a wide range of non-natural cytokine receptor hetero-dimers are competent to elicit a signaling output. We engineered synthekine ligands that assembled IL-2Rb/IL-4Ra or IL-4Ra/IFNAR2 receptor heterodimers, that do not occur naturally, triggering signaling and functional responses distinct from those activated by the endogenous cytokines IL-2, IL-4, and IFN. Furthermore, hybrid synthekine ligands that dimerized a JAK/STAT cytokine receptor with a receptor tyrosine kinase (RTK) also elicited a signaling response. Synthekines represent a new family of synthetic ligands with pre-defined receptors, but ’orphan’ functions, that enable the full combinatorial scope of dimeric signaling receptors encoded within the human genome to be exploited for basic research and drug discovery.