During cancer progression, interactions between tumor cells and immune cells play critical roles in the initiation of metastasis. In malignant melanoma, it is unclear how a melanocyte transitions from a premalignant nevus to an invasive tumor cell, and which components in the tumor microenvironment regulate this switch. A major limitation to understanding this switch in vivo is the lack of genetically tractable model systems that are amenable to high-resolution imaging of both the tumor and its microenvironment with cellular resolution. We have overcome this obstacle by directly visualizing tumor cells and their interactions with stromal cells in zebrafish. We found that injecting either human or zebrafish melanoma cells results in metastasis from the site of injection. Live imaging of the primary tumor revealed that tumor cells respond to contact with host macrophages by extending more actin-rich protrusions than those tumor cells not in contact with macrophages. Further, depleting host macrophages reduced melanoma metastasis. To reveal signaling pathways involved in macrophage-induced melanoma progression, we performed a reverse genetic in vivo screen for increased or decreased metastasis and identified myd88, a key regulator in the inflammatory response pathway, which functions downstream of Toll-Like Receptors. Depleting embryos of myd88 decreased macrophage motility and recruitment of macrophages to the primary tumor, and inhibited melanoma metastasis. We further found that expression of constitutively active Myd88 in macrophages was sufficient to induce increased melanoma metastasis. Macrophages form long, thin, and dynamic protrusions to communicate with tumor cells in vivo, and our preliminary experiments suggest that these processes may be necessary for tumor cell metastasis. We are currently testing this hypothesis, and whether expression of Myd88 affects melanoma metastasis through the formation of these dynamic protrusions in macrophages, with high-resolution imaging approaches in vivo.