Although the clinical background, gross and hematoxylin-eosin examination usually suffice for the placental diagnosis, immunohistochemistry (IHC) is essential in many cases, particularly in high-risk pregnancy. The double E-cadherin/CD34 immuno-stain is the backbone of it, particularly for diagnosing the early fetal vascular malper-fusion (FVM) characterized by the endothelial fragmentation preceding the villous hypovascularity/avascularity of distal FVM. The stain is 3–4 times more sensitive than the stromal vascular karyorrhexis, the other early FVM lesion. The endothelial fragmentation may help in timing FVM and its grading as well as in revealing its temporal heterogeneity. The immunostain makes the FVM the most common pattern of placental injury in the population of pregnancies dominated by mass-forming fetal anomalies. The immunostain is also useful in diagnosing villous hypomaturity by highlighting widened vasculosyncytial membranes. Of other immunostains, cyto-keratin IHC is invaluable for confirmation of intrauterine pregnancy in chorionic villi-negative uterine curettings. Cytokeratin and smooth muscle actin are valuable in borderline cases of shallow placental implantation. P57 immunostain is invaluable for the diagnosis of early complete hydatidiform moles. Finally, IHC may be decisive in diagnosing viral placentitis, particularly cytomegaloviral, herpetic and parvoviral.