Much progress has been made in understanding the myriad of intracellular signaling pathways responsible for control of cell physiology. Signalling downstream of receptor tyrosine kinases (RTKs) is probably the most studied signalling mechanism to date and many of the molecular components and corresponding interactions involved have been delineated. Importantly, deregulation of RTK signalling has been implicated in the formation and maintenance of many human tumours. Two of the pivotal molecular components in RTK signalling, Ras and phosphoinositide 3-kinase (PI 3-kinase), have been shown to bind to each other, leading to the activation of PI 3-kinase. However, in addition to this Ras-PI 3-kinase interaction, first described over a decade ago, several other molecular interactions have more recently been described that appear to mediate the same signal. This has brought into question the physiological relevance of the Ras-PI 3-kinase interaction during RTK signalling. Through disruption of the interaction in a mouse model, we have now confirmed that the interaction is highly functional in vivo both during mammalian development and during Ras-induced tumorigenesis. Many questions still remain: in this Perspective, we explore the remaining uncertainties surrounding the role of this signalling mechanism, as well as the future directions that will likely shed further light on its role within cells.