Metastasis is responsible for most cancer-related deaths. Chemokine receptors have been shown to aid tumor propagation at the key steps of metastasis, including the adherence of tumor cells to the endothelium, extravasation from blood vessels, colonization, angiogenesis, proliferation, and protection from the host immune response. The CXCR4/CXCL12 axis plays a major role in the homing of CXCR4 positive tumor cells to distant metastatic sites. Over the last few years, several agents have been evaluated for monitoring CXCR4 expression using PET, SPECT, and optical imaging modalities in preclinical models. This chapter discusses the current status of CXCR4-targeted probe development. As these agents become clinically available, CXCR4-based imaging could play an important role in detecting tumors with high risk for metastasis, in the early detection of metastases and in therapeutic monitoring.