Chromatin structure regulating processes mediated by the adenosine triphosphate (ATP) -dependent chromatin remodeling complex and the covalent histone-modifying complexes are critical to gene transcriptional control and normal cellular processes, including cell stemness, differentiation, and proliferation. Gene mutations, structural abnormalities, and epigenetic modifications that lead to aberrant expression of chromatin structure regulating members have been observed in most of human malignancies. Advances in next-generation sequencing (NGS) technologies in recent years have allowed in-depth study of somatic mutations in human cancer samples. The Cancer Genome Atlas (TCGA) is the largest effort to date to characterize cancer genome using NGS technology. In this review, we summarize somatic mutations of chromatin-structure regulating genes from TCGA publications and other cancer genome studies, providing an overview of genomic alterations of chromatin regulating genes in human malignancies.