Receptor tyrosine kinases (RTKs) are major regulators of key biological processes including cell growth, survival and differentiation, and were established early on as protooncogenes, with aberrant expression linked to tumor progression in many cancers. Therefore, RTKs have emerged as major targets for selective therapy with small molecule inhibitors. However, despite improvements in survival rates, it is now apparent that targeting of RTKs with selective inhibitors is only transiently effective as the majority of patients eventually become resistant to therapy. As chemoresistance is the leading cause of cancer spread, progression and mortality, there is an increasing need for understanding the mechanisms by which cancer cells can evade therapy-induced cell death. The TAM (Tyro3, Axl, Mer) subfamily of RTKs in particular feature in a variety of cancer types that have developed resistance to a broad range of therapeutic agents, including both targeted as well as conventional chemotherapeutics. This article reviews the roles of TAMs as tumor drivers and as mediators of chemoresistance, and the potential effectiveness of targeting them as part of therapeutic strategies to delay or combat resistance.