Chromatin-regulating proteins modulate nucleosome structure by either modifying histones covalently or disrupting DNA-protein interaction directly with ATP hydrolysis. Evidence has shown that chromatin-regulating proteins play critical roles in regulation of molecular processes using DNA as template, including gene expression, DNA replication, DNA damage repair, and chromosome integrity. In most of human malignancies, chromatin-regulating proteins have been shown as functional oncogenes. In some scenarios, chromatin-regulating proteins also could have tumor suppressive functions. Thereby, small molecular inhibitors targeting chromatin-regulating proteins could be used for cancer therapies. Numerous small molecular inhibitors against chromatin-regulating proteins are recently developed by academic and industrial groups. These compounds are evaluated for antitumor effects in vitro and in vivo. Some of them have shown great potential to become a therapeutic drug for cancer, and is currently evaluated in clinical trials. A few compounds have been approved for clinical use in cancer treatment. In this review, we will focus on the recent progress on the development of small inhibitors of chromatin-regulating proteins for cancer therapy.