The lymphatic system is fundamentally important to cardiovascular disease, infection and immunity, cancer, and probably obesity — the four major challenges in healthcare in the 21st century. This Review will consider the manner in which new knowledge of lymphatic genes and molecular mechanisms has demonstrated that lymphatic dysfunction should no longer be considered a passive bystander in disease but rather an active player in many pathological processes and, therefore, a genuine target for future therapeutic developments. The specific roles of the lymphatic system in edema, genetic aspects of primary lymphedema, infection (cellulitis/erysipelas), Crohn’s disease, obesity, cancer, and cancer-related lymphedema are highlighted.