While the cardiovascular system acts as the major circulatory system in the human body, the existence of a parallel, almost equally important, secondary circulatory system is frequently overlooked. This system is called the lymphatic system, which serves to perform three primary functions in the human body: (1) drainage of interstitial fluid, (2) transport of immune cells, and (3) transport of lipid. These three functions are performed with the help of an intricate network of vessels and nodes, called the lymphatic system. The lymphatic system has its own unique anatomy and physiology that interacts with, and is influenced by, its local mechanical microenvironment. In this review, we will highlight studies that have delineated the molecular mechanisms underlying the mechanosensitivity of the lymphatics and the role of mechanomodulation on lymphatic development, physiology and pathophysiology. These topics will be explored in the context of early development, postnatal development and maturation, normal physiology, and disease.