The aortic heart valve is a complex and sophisticated structure that functions in a mechanically challenging environment. With each cardiac cycle, blood flow exerts shear stresses, bending stress and tensile and compressive forces on the valve tissue. These forces determine a plethora of biological responses, including gene expression, protein activation and cell phenotype. Consequently, mechanical forces may influence valve remodeling or pathological changes. Understanding the mechanobiology of heart valves is a vast task. Herein, some of the recent studies that have increased current knowledge of endothelial and interstitial cell interactions with physical forces are examined. Additionally, experimental co-culture models are described that are being developed to further improve the understanding of endothelial-interstitial cell interactions. Finally, the means by which organ culture systems are being utilized to study heart valve biology, thereby providing a complementary approach to in vivo experimentation, are described.