The current knowledge regarding ADP-ribosylation modifications of histones, particularly mono-ADP-ribosylation modifications, is limited. However, recent studies have identified an increasing number of mono-ADP-ribosyltransferases and the role of mono-ADP-ribosylation has become a hot research topic. In particular, histones that are substrates of several mono-ADP-ribosyltransferases and mono-ADP-ribosylated histones were indicated to be involved in numerous physiological or pathological processes. Compared to poly-ADP-ribosylation histone modification, the use of mono-ADP-ribosylation histone modification is restricted by the limited methods for research into its function in physiological or pathological processes. The aim of the present review was to discuss the details regarding mono-ADP-ribosylation modification of histones and the currently known functions thereof, such as cell physiological and pathological processes, including tumorigenesis.