Background: The CCAAT/enhancer binding proteins (C/EBPs) form a family of transcription factors regulating many genes’ expression in a variety of cells/tissues/organs at different developmental stages. With their capability of binding to their cognate DNA elements and through protein-protein interactions, C/EBPs modulate diverse functions including cell differentiation, metabolism, and immune response, under both physiological and pathological conditions such as the establishment of hematological lineages, the maintenance of normal reproductive function, and the development of malignancies.Objectives: This review concentrates on the role(s) and epigenetic alterations of C/EBP genes in hematologic malignancies and gynecologic organs and disorders. New research findings on molecular pathways involved in C/EBP function and regulation are reviewed and analyzed. The potential therapeutic values of these findings are also discussed. Conclusion: Unlike in hematologic malignancies in which C/EBP mutations and their disruption of wild type C/EBP tumor suppressive activities have been well documented, mutation of C/EBP does not appear to be a common event in gynecologic cancers, raising some doubt if C/EBPs may have tumor suppressor activity in gynecologic cancers. However, this notion could not exclude the possibility that downregulation or DNA methylation-meditated epigenetic silencing of C/EBPs may contribute to the development of gynecologic malignancies.