H19 is an oncofetal transcript with crucial roles in the development and progression of several neoplastic cells. With anti-apoptotic, pro-proliferative, and pro-migratory functions, H19 affects the carcinogenic process from different functional points. In addition, H19 has central roles in the induction of chemoresistance in breast cancer, lung cancer, glioma, liver cancer, and other types of cancers. Induction of EMT, activation of oncogenic signaling pathways, and changes in the tumor microenvironment are among mechanisms of participation of H19 in chemoresistance. Paclitaxel, doxorubicin, tamoxifen, erlotinib, gefitinib, temozolomide, and methotrexate are among therapeutic agents whose efficacy is influenced by the expression of H19. In the present paper, we discuss the impact of H19 in conferring resistance to chemotherapeutic agents in different cancers.