The mitral valve exists in a mechanically demanding environment, with the stress of each cardiac cycle deforming and shearing the native fibroblasts and endothelial cells. Cells and their extracellular matrix exhibit a dynamic reciprocity in the growth and formation of tissue through mechanotransduction and continuously adapt to physical cues in their environment through gene, protein, and cytokine expression. Valve disease is the most common congenital heart defect with watchful waiting and valve replacement surgery the only treatment option. Mitral valve disease (MVD) has been linked to a variety of mechano-active genes ranging from extracellular components, mechanotransductive elements, and cytoplasmic and nuclear transcription factors. Specialized cell receptors, such as adherens junctions, cadherins, integrins, primary cilia, ion channels, caveolae, and the glycocalyx, convert mechanical cues into biochemical responses via a complex of mechanoresponsive elements, shared signaling modalities, and integrated frameworks. Understanding mechanosensing and transduction in mitral valve-specific cells may allow us to discover unique signal transduction pathways between cells and their environment, leading to cell or tissue specific mechanically targeted therapeutics for MVD.