Genetic aberrations and epigenetic alterations are recognized to be indispensable for cancer development. Histones are vital epigenetic components that form strong electrostatic interactions with DNA and condense it into chromatin. To initiate all DNA-templated processes, chromatin architecture is modulated by addition or removal of posttranslational modifications (PTMs) of histones, thereby altering the affinity of histones with DNA. Single or multiple posttranslational modifications in combination have the propensity to recruit specific protein/complexes onto chromatin to mediate diverse cellular processes by altering gene expression. Interestingly, few of these posttranslational modifications of histones have been strongly linked to cancer and are referred to as “histone oncomodifications,” with respective alteration in their modifying enzymes. Thus, it becomes imperative to identify variations in global levels of histone marks and their modifying enzymes in different pathophysiological states such as cancer and to explore the utility of these differences in management of cancer and better clinical outcome.