PRDM2/RIZ is a histone methyltransferase that belongs to the Positive Regulatory Domain I-binding factor 1 (PRDM) superfamily, identified by a PR domain with methyltransferase activity and by zinc finger domains. Among PRDM members, PRDM2 represents a relevant member that has emerged as a dynamic player in the intricate cancer biology landscape. As observed for other PRDMs, two main proteins differing by the PR domain, RIZ1 and RIZ2, are encoded by the PRDM2 locus. The imbalance in the RIZ1/RIZ2 amounts could be responsible for several malignancies. Different reports, indeed, highlight a yin-yang behavior, supporting a tumor suppressor and an oncogene role for RIZ1 and RIZ2, respectively. Moreover, a tight connection among PRDM2 and estrogen receptor α exists. Interestingly, RIZ1 represents an important downstream target of estradiol/estradiol receptor action and RIZ2 is an estrogen-responsive gene. Recently, novel insights have been added on the putative oncogene role of RIZ2; however, additional studies are strongly needed to elucidate the subtending molecular mechanisms. The RIZ2 overexpression, indeed, increased oncogenicity of both HEK-293 and DLD1 cell lines, by regulating several crucial genes involved in many cancer-related pathways, as revealed by transcriptome studies. Besides, RIZ2 induced EGF pathway deregulation in colon cancer cells. This comprehensive chapter delves into the multifaceted PRDM2 roles in several cancer types, exploring its impact on crucial cellular processes, its intricate interactions with signaling pathways, and its potential as a diagnostic and therapeutic target.