Although many potential biomarkers for colorectal cancer (CRC) have been detected, rarely do they have usage in clinical practice. New biomarkers are needed to detect CRC at an early phase, to detect recurrence and monitor therapeutic response. It has become increasingly evident that altered epigenetic control of gene expression plays an important role in carcinogenesis. In addition to DNA methylation and non-coding RNAs, post-translational histone modifications play an important role in gene regulation and carcinogenesis. Knowledge regarding the patterns of histone modifications in CRC is accumulating. Additionally, histone modification alterations can be detected in nucleosomes circulating in the blood of patients with cancer offering the possibility to use them as biomarkers in CRC and other types of cancer. In the present review, we discuss the potential clinical utility of histone modifications in circulating nucleosomes for the diagnosis and estimation of prognosis in patients with CRC.