Cells maintain a steep Ca²⁺ ion concentration gradient between the cytosol and the extracellular space, allowing Ca²⁺ to operate as a universal second messenger mobilized from internal stores and the extracellular medium. In the early 1970s it was found that normal cells require extracellular Ca²⁺ to undergo cell proliferation, as least in vitro.Other studies demonstrated that in vivo extracellular Ca²⁺ gradients regulated cell proliferation and differentiation in tissues e.g. the epidermis and colonic epithelium. Ca²⁺ starvation of non-tumourigenic cells in culture induced cell cycle withdrawal, yet transformation by just a single oncogene such as the small GTPase Ras – bypassed the need for a Ca²⁺ source to drive cell proliferation.Oncogenic Ras GTPases are found in approximately 15% of human tumours and are known to be necessary and sufficient for tumour induction and maintenance in cancer models e.g. lung adenocarcinoma. These mutant proteins have defective GTPase activity, normally controlled by the binding of GTPase-activating proteins (GAPs), to which oncogenic Ras is insensitive. The canonical view of Ras signalling focuses on receptor/non-receptor tyrosine kinase signalling cascades where a Ras GEF (SOS) is recruited via adapters to the receptor in order to activate Ras at the plasma membrane. Ras is deactivated by the recruitment of p120 Ras GAP via SH2 domains to phosphotyrosine residues on the activated receptor. The delineation of this pathway a decade ago was a major advance in signal transduction research. More recently, multiple families of Ras GEFs (GRF and GRP/CalDAG-GEF) and Ras GAPs (SynGAP and GAP1) have been identified and several of these proteins appear to be regulated dynamically by diacylglycerol (DAG) and/or Ca²⁺ – each a ‘product’ of phospholipase C (PLC) signalling. Concurrently a novel class of PLC, PLCε, was discovered which operates as a Ras effector in some contexts. Thus, a battery of potential Ras signalling modulators converges with PLC-dependent second messenger pathways.Recently, Ca²⁺ has been directly implicated in the control of Ras cycling with the discovery of twin Ca²⁺ triggered Ras GAPs: RASAL (Ras GTPase-activating-like) and CAPRI (Ca²⁺-promoted Ras inactivator). I will present work from our lab that demonstrates their intrinsic Ras GAP function using cellular reporter assays of the Ras activation state, combined with spatio-temporal analysis of Ca²⁺-triggered CAPRI/RASAL translocation. CAPRI and RASAL are dynamic C2 domain-dependent Ca²⁺ sensors, like conventional protein kinase C (PKC) and cytosolic phospholipase A2. We have discovered that these GAPs sense Ca²⁺ signals very differently. Thus, it seems likely that CAPRI and RASAL play novel roles in the information processing of Ca²⁺ signals at the level of the Ras GTPase.