Primary lymphedema is a phenotypic manifestation caused by a genetic mutation. The genes currently recognized, if mutated, as responsible for the disease are different, and the same mutations affect in a diversified and often complex way (monogenic, polygenic, somatic mutation). There are familial, sporadic, and syndromic forms of lymphedema. In all three cases, genetic mutations that intervene in the determinism of the pathology have been described. The genes most frequently called into question as responsible for both familial forms and syndromes are VEGFR3 or FLT4 and FOXC2. Currently, more than 30 genes have been identified that, if mutated, can cause lymphoedema. But in the genetic study, important polymorphisms of certain genes are continually being identified, which, with further investigation by means of the ‘segregation study’ of the mutation aspects in the proband’s blood relatives, sometimes allows new candidate genes to be identified. Once the same polymorphism has been identified in the blood relative, it can be studied by lymphoscintigraphic investigation, which in some cases shows a partial defect in the development of the lymphatic system in subclinical patients, confirming the heritability of the disease and the validity of the gene responsible for the disease.