CRIPTO is a GPI-anchored cell surface protein functioning as an obligatory coreceptor for Nodal and growth differentiation factors (GDF1/3) signaling 1. Cell-associated CRIPTO acts in cis (autocrine), while shedding produces soluble CRIPTO acting in trans (paracrine) on other cells 2. CRIPTO activates ALK4/ALK7 signaling through both Smad-dependent pathways (Smads 2, 3, 4) and non-Smad pathways (PI3K, Akt, MAPK), with GRP78 as an essential cofactor 1. It also facilitates Wnt/β-catenin and Notch signaling as a chaperone protein 1. Essential during embryonic development for anterior-posterior axis formation and precardiac mesoderm differentiation 3, CRIPTO is re-expressed in most epithelial cancers including lung, gastric, pancreatic, and breast carcinomas 3. In malignancy, CRIPTO promotes cancer stem cell survival, epithelial-mesenchymal transition (EMT), migration, invasion, and angiogenesis 4. High CRIPTO expression correlates with TNM staging, lymph node metastasis, and malignant progression in lung adenocarcinoma 5. In pulmonary arterial hypertension, elevated CRIPTO expression occurs in vascular endothelial and smooth muscle layers 6. CRIPTO represents an attractive therapeutic target for cancer immunotherapy and other diseases, with humanized anti-CRIPTO antibodies in clinical trials 4.