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Metastatic progression, which begins with the invasion and migration of tumor cells from a primary tumor, marks a major turning point in the evolution of cancer. Indeed, it eventually leads to the formation of secondary tumors, the metastases, which are very often responsible for the patient’s death. Understanding the mechanisms controlling the different steps of this process, as well as those explaining the fundamental phenomenon of organotropism (i.e. the distribution of metastases in distant organs by a non-random and tumor-specific process), is essential to define new innovative therapeutic solutions. In this review paper, we will present how biomechanics is an essential element to this understanding, and will emphasize the importance of this orthogonal and promising angle of study as well as our laboratory’s focus on the late stages of dissemination, arrest and extravasation of circulating cancer cells and factors secreted by the primary tumor such as extracellular vesicles.