Hydatidiform moles are non-neoplastic proliferations of the villous trophoblasts, with two distinct subtypes: complete (CHM) and partial hydatidiform moles (PHM). While they share some basic features, that is, hydropic placenta/chorionic villi and trophoblastic hyperplasia; partial and complete moles have significant differences in their genetic composition, clinical presentation, histomorphology, and the subsequent risk of developing persistent gestational trophoblastic disease (GTD) and gestational trophoblastic neoplasia (GTN). At the genetic level, PHM are typically diandric monogynic triploid gestations, most often arising from two sperms fertilizing an egg. Complete moles, on the other hand, are most commonly diploid or tetraploid and are entirely paternally derived, with rare exceptions of familial biparental complete moles. Although cytogenetic abnormalities, including triploidy, have been reported in hydatidiform moles since the 1960s, the two subtypes—complete and partial moles—were not defined and separated until the late 1970s. Initially, the basis of division had been the absence or presence of an embryo/fetus; and partial (or “incomplete”) moles were defined as “moles with fetuses” (alive or dead) with a triploid karyotype, slowly progressing hydatidiform swelling of the placenta with focal sparing of villi, and focal, inconspicuous trophoblastic hyperplasia. Over the past three decades, the evolution of ancillary techniques—cytogenetics, flow cytometry, immunohistochemistry, and most recently molecular genotyping—has significantly contributed to our understanding of the pathogenesis and biology of complete and partial hydatidiform moles and improved our diagnostic accuracy, as it will be discussed in detail in this chapter.