TAM (Tyro3-Axl-Mer) receptor tyrosine kinases and Met are implicated in several hallmarks of cancer progression including sustained angiogenesis, enhanced motility, tissue invasion and acquisition of metastatic potential through the upregulation of epithelial-to-mesenchymal transition. Increasing evidence has confirmed Axl and Met as emerging central drivers of adaptive resistance to targeted therapies across a wide variety of cancers. In this issue of Oncogene, Zhou et al. describe the mechanisms linking Axl and Met activation to acquired resistance to sunitinib in renal cell carcinoma (RCC), providing a pre-clinical rationale for the development of Axl and Met inhibitors including cabozantinib in anti-angiogenic resistant RCC.