CLEC14A is a transmembrane C-type lectin domain protein primarily expressed on vascular endothelial cells that regulates angiogenesis and lymphangiogenesis through modulation of VEGF receptor signaling. 1 CLEC14A functions as a fine-tuner of vascular homeostasis by forming complexes with VEGFR-2 and VEGFR-3, with CLEC14A deficiency leading to increased VEGFR-2 signaling and enhanced angiogenic sprouting. 1 The protein interacts with extracellular matrix proteins including MMRN2, and this interaction is critical for regulating sprouting angiogenesis initiation during vascular development. 2 CLEC14A also interacts with heat shock protein HSP70-1A to modulate ERK phosphorylation and endothelial tube formation. 3 During embryonic development, CLEC14A is a venous endothelial marker that genetically interacts with Etv2 and Vegf signaling during vasculogenesis. 4 5 Clinically, CLEC14A expression is markedly elevated in solid tumors including hepatocellular carcinoma and renal cell carcinoma compared to healthy tissue, making it a potential therapeutic target and diagnostic biomarker. 6 7 Paradoxically, in lung adenocarcinoma, CLEC14A acts as a tumor suppressor when methylation-induced downregulation is prevented. 8