The identification of the causes of cancer at the cellular level has led to the discovery of the Epidermal Growth Factor Receptor (EGFR)/Ras/Mitogen-Activated Protein Kinase (MAPK) signaling pathway as a target for the development of anti-cancer strategies. A variety of therapeutic approaches to inhibit the EGFR/Ras/MAP module are currently being tested in clinical trials or have even been approved for the treatment of some tumors. However, more efficient ways to block the EGFR/Ras/MAPK pathway in tumor cells still have to be developed. The subcellular localisation of each member of this module is of pertinent importance to ensure signaling. Accumulating evidence suggests that targeting/scaffold proteins regulate the assembly, localization and activity of EGFR/Ras/MAPK signal transduction components. In particular proteins that stimulate the lysosomal downregulation of the EGFR and the targeting of Ras regulators/effectors to Ras could contribute to improve strategies to inhibit EGFR/Ras signaling in cancer. These proteins include the Cbl/CIN85/endophilin pathway, caveolin, galectins, annexins, Impedes Mitogenic Signal Propagation (IMP), 14-3-3 and Kinase Suppressor of Ras (KSR). Here we will review the current literature regarding the potential of targeting/scaffold proteins to affect the lysosomal targeting of EGFR and the subcellular localization of the Ras/MAPK signaling cascade.