Based on these considerations, continuous design and improvement of new scaffold molecules targeting DOT1L are still sought after, since they held the promise to be exploitable not only against leukemias, where they were first studied, but also for treatment of solid cancers, where as summarized in this review this enzyme has been shown to be a key regulator of several basic mechanisms controlling carcinogenesis, tumor growth, and metastatization. This evidence concerns the gene DOT1L and leukemia.