Chronic secondary lymphedema is a potentially devastating condition affecting 90-150 million people worldwide. In the US, lymphedema is most commonly encountered in the upper extremity of women who have undergone axillary lymph node dissection for staging and treatment of breast cancer, though it may also occur following lymph node dissection for melanoma as well as certain gynecology oncologic operations. While a great deal has been elucidated about the biology of lymphatics, lymphatic development, and the lymphatic system in the past 20 years, considerably less is known about impaired lymphatic regeneration and the mechanisms that lead to secondary lymphedema. This deficit in knowledge presents a barrier to the development of effective treatments or prophylactic measures for chronic secondary lymphedema. Recent advances in this arena have showed that pathogenesis of lymphedema is complex, and that effective treatments for this often devastating condition will likely require the use of multiple modalities. In this review, we will discuss the development, anatomy, and physiology of lymphatics as means of introducing this system to the reader. Further, the latest advances in the scientific exploration of lymphedema and lymphatic regeneration will be presented.