Epigenetic regulators play a critical role in cancer initiation, progression, and resistance. A growing body of evidence has highlighted an important role for numerous histone post-translational modifications and their mediators in driving various aspects of tumorigenesis, metastatic progression, therapeutic resistance and immune evasion. This chapter provides an in-depth review of both well-characterized and less common histone modifications such as acetylation, methylation, phosphorylation, and ubiquitination, and the functional contribution of their mediators in solid tumors and hematopoietic malignancies. We delve into the mechanisms by which these histone modifications regulate chromatin dynamics and gene expression programs leading to plasticity and evolution of cancer. Furthermore, we highlight the clinical significance and the potential of targeting these epigenetic regulators with small molecule inhibitors either alone or in combination with conventional therapies and immunotherapies as a promising strategy for treating various cancers and improving patient outcomes.