In the event of metastatic disease, emergence of a lesion can occur at varying intervals from diagnosis and in some cases following successful treatment of the primary tumor. Genetic factors that drive metastatic progression have been identified, such as those involved in cell adhesion, signaling, extravasation and metabolism. However, organ specific biophysical cues may be a potent contributor to the establishment of these secondary lesions. We combine a novel preclinical model of metastasis with a suite of biophysical tools to elucidate the role of tissue biophysical properties of in the establishment of metastatic lesions in vivo. Specifically, I will discuss our efforts to determine what physical cues influence disseminated tumor cells in different organ microenvironments using in vitro and in vivo preclinical models such as 3D culture systems and zebrafish.