Calmodulin (CaM) uniquely promotes signaling by oncogenic K-Ras, but not by N-Ras or H-Ras. How CaM interacts with K-Ras and how this stimulates cell proliferation are among the most challenging questions in KRAS-driven cancers. Earlier data pointed to the formation of a ternary complex consisting of K-Ras, phosphatidylinositide-3-kinase α (PI3Kα), and CaM. Recent data indicate that phosphorylated CaM binds to the Src homology 2 (SH2) domains of the p85 subunit of PI3Kα and activates it. Modeling suggests that the high-affinity interaction between the phosphorylated CaM tyrosine motif and PI3Kα can promote full PI3Kα activation by oncogenic K-Ras. This review discusses the role of CaM in PI3K signaling at the membrane in KRAS-driven cancers. This is significant because it may help the development of K-Ras-specific pharmacology.