The Ras GTPases are frequently mutated in human cancer and although the Raf kinases are essential effectors of Ras signaling, the tumorigenic properties of specific Ras-Raf complexes are not well characterized. This study examines the ability of individual Ras and Raf proteins to interact in live cells using bioluminescence resonance energy transfer (BRET) technology. The BRET system allows quantitative measurements to be obtained under conditions that preserve crucial features of Ras and Raf regulation, including lipid processing, intracellular trafficking, membrane microdomain targeting, and protein phosphorylation. Strikingly, our findings demonstrate pronounced binding preferences between the Ras and Raf family members. We find that while C-Raf and K-Ras can bind with high affinity to all Ras or Raf family members respectively, H-Ras displays preferential binding to C-Raf whereas B-Raf exhibits a striking selectivity for K-Ras. The B-Raf selectivity is mediated by the acidic, N-terminal segment of B-Raf and requires the K-Ras polybasic region for high-affinity binding. This study also finds that C-Raf is required for mutant H-Ras-driven signaling and that events inducing stable B-Raf/C-Raf dimer formation, such as Raf inhibitor treatment or certain B-Raf mutations, allow mutant H-Ras to engage B-Raf with increased affinity to promote ERK activation and tumorigenesis.