Lymphatic vessels constitute a ubiquitous countercurrent system to the blood vasculature that returns interstitial fluid, salts, small molecules, resorbed fat, and cells to the bloodstream. They serve as conduits to lymph nodes and are essential for multiple physiologic activities. However, they are also hijacked by cancer cells to establish initial lymph node metastases, as well as by infectious agents and parasites. Despite these obvious important functions in human pathologies, a more detailed understanding of the molecular mechanisms involved in the regulation of the lymphatic vasculature has trailed that of the blood vasculature for many years, mainly because critical specific characteristics of lymphatic endothelial cells were discovered only recently. In this Review series, several major aspects of the active and passive involvement of the lymphatic vasculature in human disease and physiology are presented, with a focus on translational findings.