AbstractIn molecular cancer therapeutics only 10% of known cancer gene products are targetable with current pharmacological agents. Major oncogenic drivers, such as MYC and KRAS proteins are frequently highly overexpressed or mutated in multiple human malignancies. However, despite their key role in oncogenesis, these proteins are hard to target with traditional small molecule drugs due to their large, featureless protein interfaces and lack of deep pockets. In addition, they are inaccessible to large biologicals, which are unable to cross cell membranes. Designer interference peptides (iPeps) represent emerging pharmacological agents created to block selective interactions between protein partners that are difficult to target with conventional small molecule chemicals or with large biologicals. iPeps have demonstrated successful inhibition of multiple oncogenic drivers with some now entering clinical settings. However, the clinical translation of iPeps has been hampered by certain intrinsic limitations including intracellular localization, targeting tissue specificity and pharmacological potency. Herein, we outline recent advances for the selective inhibition of major cancer oncoproteins via iPep approaches and discuss the development of multimodal peptides to overcome limitations of the first generations of iPeps. Since many protein–protein interfaces are cell-type specific, this approach opens the door to novel programmable, precision medicine tools in cancer research and treatment for selective manipulation and reprogramming of the cancer cell oncoproteome.