Receptor tyrosine kinases (RTKs) represent a family of cell surface receptors that have been shown not only to play a key role in regulating normal cellular processes, but also to be critical in the development and progression of many types of human cancer. To date, many crystal structures of individual domains of RTKs are available; however, the high resolution structural information for full‐length RTK proteins either in their apo‐state or in ligand‐bound states remains elusive. In addition, there are no structural detail about how the active full‐length receptor can bind the effector protein for the activation of downstream signaling pathway. Lacking a complete structure of full‐length receptor signaling complex hinder our understanding of how this important protein functions. We determine the structures of full‐length RTK proteins, in complex with their ligands and downstream proteins, by single particle cryo‐EM, as key to understand the critical role that this protein family plays in the physiology of the cell. Epidermal growth factor receptor (EGFR), RET, cMET and Insulin receptor (IR), the most studied members in the RTK family, are chosen as the targets for structure determination. These pathways comprise a complex and diverse signaling network, and play an essential role in normal cell proliferation, differentiation, development and motility. Aberrant activation can lead to both tumor growth and metastatic progression of cancer cells, which makes them promising candidate for cancer therapy. Determination of full‐length RTKs in apo‐ and ligand‐bound states shed light on its mechanisms of kinase activation, enhance understanding of the interaction between receptor and their ligand and inhibitors, and facilitate development of selective anti‐cancer drugs. Reconstitution of fully assembled signaling complex reveal the mechanism by which the active receptors initialize the downstream signaling transudation, and provide direct structural evidence for how the plasma membrane plays roles in this processing. Solving the structures of different members of the RTK family reveal similarities and differences in the structure‐function relationships within this receptor family, which can potentially lead to new strategies to selectively inhibit/modulate individual pathways for cancer therapy or concurrently target various pathways, an approach that has been suggested to improve therapeutic effectiveness.Support or Funding Informationthe Welch foundation, and CPRIT foundationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.