Epigenetic states determine gene expression patterns during differentiation and organismal development. These heritable states are layered on top of the genetic information, which is the same in every cell irrespective of the differentiation program it follows. Epigenetic states are, while usually established by a DNA sequence-specific signal (such as the action of a transcription factor), maintained or propagated in the absence of DNA-sequence specific factors. The molecular basis of such cellular memory has remained elusive, yet histones, the proteins that package DNA into chromatin, have been recognized as a prime candidate for epigenetic regulation. The wealth of known histone posttranslational modifications (marks) and combinations thereof highlight the verbose coding potential of chromatin for epigenetic information. With the advent of epigenomics, histone modifications have been studies in many aspects of human disease – pre and postnatal development, behaviour, memory and neurodegeneration, genome stability and cancer, diabetes and cardiovascular diseases, AIDS, stem cells and reprogramming. However, it has been noted that our current, descriptive methodologies do not rule out the possibility that histones are mere bystanders rather than culprits in many pathologies. For example, it is disputed that histone marks, and ultimately the underlying histone moiety, have a long lifetime, and are inherited faithfully during DNA replication. In the absence of unequivocal proof of locus-specific histone inheritance, the epigenetic nature of their marks remains debatable. It is therefore a major challenge of our field to devise experiments that can directly and conclusively test this hypothesis.