How do Ras isoforms attain oncogenic specificity at the membrane? Oncogenic KRas, HRas, and NRas (K-Ras, H-Ras, and NRas) differentially populate distinct cancers. How they selectively activate effectors and why is KRas4B the most prevalent are highly significant questions. Here, we consider determinants that may bias isoform-specific effector activation and signaling at the membrane. We merge functional data with a conformational view to provide mechanistic insight. Cell-specific expression levels, pathway cross-talk, and distinct interactions are the key, but conformational trends can modulate selectivity. There are two major pathways in oncogenic Ras-driven proliferation: MAPK (Raf/MEK/ERK) and PI3Ka/Akt/mTOR. All membrane-anchored, proximally located, oncogenic Ras isoforms can promote Raf dimerization and fully activate MAPK signaling. So why the differential statistics of oncogenic isoforms in distinct cancers and what makes KRas so highly oncogenic? Many cell-specific factors may be at play, including higher KRAS mRNA levels. As a key factor, we suggest that because only KRas4B binds calmodulin, only KRas can fully activate PI3Ka/Akt signaling. We propose that full activation of both MAPK and PI3Ka/Akt proliferative pathways by oncogenic KRas4B—but not by HRas or NRas—may help explain why the KRas4B isoform is especially highly populated in certain cancers. We further discuss pharmacologic implications.