Lymphedema is characterized by the swelling of extremities due to the accumulation of interstitial fluids. It is a painful and devastating disease that increases the risk of infections and destroys patients' quality of life. Secondary lymphedema is caused by damage to the lymphatic system due to infections, obesity, surgery, and cancer treatments. This damage fails to be repaired and leads to fluid accumulation, tissue remodeling, inflammation, and ultimately fibrosis. The lymphedema microenvironment is altered by stress, immune dysfunction, and changes in metabolism. Stress in the microenvironment includes increased hypoxia and oxidative stress but how this contributes to lymphedema progression is unclear. The immune system plays a critical role in lymphedema through T cell helper type 2 (Th2) immune responses and the infiltration of macrophages into lymphedematous tissue. The inflammatory cytokines released by immune cells lead to tissue remodeling and fibrosis. There are also changes in metabolism in the lymphedema microenvironment with altered lipid oxidation, ketone body oxidation, and glycolysis. How these changes affect lymphedema and treatment interventions has been the focus of clinical trials. Lymphedema is also associated with cancer and obesity through damage to the lymphatic system. This review will illustrate microenvironmental changes in lymphedema and how this relates to cancer and obesity. In addition, we will discuss new therapeutic strategies to treat lymphedema. Finally, we will address the prospects of lymphedema research in the context of the microenvironment.