Significance KRAS encodes two protein isoforms which differ in intracellular trafficking and plasma membrane location. Moreover, KRAS mutations in cancer activate both isoforms. Thus, understanding their individual contributions to tumor development may facilitate the design of therapeutic strategies to selectively target each isoform. Here, we describe two strains of mice that fail to express KRAS4B without affecting expression of either wild-type KRAS4A or oncogenic KRAS4A ^G12V . Expression of KRAS4A in the absence of KRAS4B prevents postnatal development. More importantly, expression of the endogenous KRAS4A ^G12V isoform in the absence of KRAS4B is sufficient to induce lung adenocarcinomas that undergo proximal metastasis. Hence, development of therapeutic strategies against KRAS mutant tumors must take into account inhibition of both protein isoforms.