Microvesicles are small, membrane-bound vesicles that are shed from the plasma membrane of cells into the extracellular space. Microvesicles contain a variety of cargo not typically thought to be released from cells, including receptor tyrosine kinases, cytosolic signaling proteins, and microRNAs, which are transferred from donor cells to recipient cells. The transfer of microvesicle cargo can result in the transformation of recipient cells thereby supporting disease progression, including modified fibroblast metabolism, epithelial cell contractility, vascular remodeling, and immune cell inflammatory signaling. Additionally, microvesicles are believed to play prominent roles in cell-cell communication and disease progression as they are detected at elevated concentrations in diseased tissues. As microvesicle uptake by recipient cells can modulate cell function to promote disease progression, understanding the mechanisms and mechanosensitivity of microvesicle release, internalization, and the resulting signaling is crucial to fully comprehend their functions in disease. Here, we review recent advances in the understanding of actomyosin-regulated microvesicle biogenesis, microvesicle uptake via pinocytosis, and the resulting cellular transformation. We discuss the effects of altered cell contractility, mode of cell migration, and extracellular matrix compliance on microvesicle signaling, with direct implications in disease progression and identifying future therapeutic targets.