Receptor tyrosine kinases (RTKs) such as the insulin-like growth factor type 1 receptor (IGF-1R) control important biological activities as well as being involved in pathological processes. Due to their supportive nature in many human cancers they have long been considered attractive therapeutic targets. However, lessons learnt from early targeting trials highlight that a simple “active versus inactive” state model with classical kinase-only signaling is overly simplistic and does not describe reality. A vast amount of evidence exists disproving this model and hence provides a rational explanation for failure of many targeting agents designed under such a paradigm. In addition, substantial evidence exists that the IGF-1R and other RTKs make direct use of the G protein-coupled receptor (GPCR) components G proteins, GRKs, and β-arrestins, outside of their traditional receptor family frame. In this chapter we review the evidence that RTKs can undertake a wide range of active conformations, capable of distinct downstream signal cascades and propose an RTK/GPCR functional hybrid model, while discussing the implications of such an update on therapeutic drug development pipelines.