The receptor tyrosine kinases Axl and Mer subserve the process of termination of proinflammatory signaling and have key roles in both the resolution of inflammation and restoration of homeostasis. Axl functions prominently under conditions of tissue stress or in response to infection, whereas Mer has a major role in maintenance of homeostasis within tissues. Distinct patterns of expression of Axl and Mer underlie their clearly defined functional roles during the initiation and progression of inflammation. Axl and Mer are expressed by tumor cells and by infiltrating inflammatory cells and the regulation of cellular function via Axl and Mer signaling is also important for tumorigenesis, tumor progression, and metastasis. In this review, we consider the divergent functions of Axl and Mer in the context of inflammatory processes within tumors and the implications for development of therapeutic agents targeting these receptors.