The lymphatic vasculature is crucial for maintaining tissue-fluid homeostasis, providing immune surveillance and mediating lipid absorption. The lymphatic vasculature is tightly associated with the blood vasculature, although it exhibits distinct morphological and functional features. Endothelial cells (ECs) lineage fate specification is determined during embryonic development; however, accumulating evidence suggests that differentiated ECs exhibit remarkable heterogeneity and plasticity. In this review, we provide an overview of the molecular mechanisms promoting lymphatic cell fate specification in the mammalian embryo. We also summarize available data suggesting that lymphatic EC fate is reprogrammable in normal and pathological settings. We further discuss the possible advantages of cell fate manipulation to treat certain disorders associated with lymphatic dysfunction.