Lymphedema, defined as the abnormal accumulation of protein-rich fluid in soft tissues, results from the dysfunction of lymphatic system, an imbalance between lymph formation and its absorption into the initial lymphatics. Primary lymphedema occurs rarely on idiopathic or developmental abnormalities, especially hypoplasia or aplasia of lymphatics. Secondary lymphedema commonly develops when lymph transport is impaired due to lymphatic damage or resection of lymph nodes in surgery, infection, and radiation. Lymphatic endothelial cells (LECs) actively participate in the phenotypic consequences of a deranged lymphangiogenesis relating to tissue fluid accumulation in the pathogenesis of lymphedema. Recent insights into molecular genetic bases have shown an updated genotype-phenotype correlation between lymphangiogenesis, lymphatic function, and lymphedema. FOXC2, EphrinB2, VEGFR-3, VEGF-C, angiopoietin-2, Prox-1 and podoplanin have proved to be important factors of the genetic cascade linking to hereditary lymphedema, and embryonic and postnatal lymphatic development. FOXC2 may have a key role in regulating interactions between LECs and smooth muscle cells, and in the morphogenesis of lymphatic valves. Reduced VEGFR-3 tyrosine kinase activity and subsequent failure in transducing sufficient physiological VEGF-C/-D signals may affect LEC function and structure in the intercellular junctions and peri-lymphatic components. Identification of genetic markers in humans and animal models would facilitate the management of environmental factors influencing the expression and severity of lymphedema, and provide a basis for developing novel targeted therapies for the disease.