Space exploration is moving toward the next milestone: space colonization. The risks for human health, associated to the permanence in the space, are already object of studies by several experiments both in orbit and, under simulated space conditions, on hearth. Now, these assessments will need to be extended over the increased permanence, in view of the stable life on other planets. It is well known that the environmental conditions present in the space, primarily related to the altered gravity, introduce a physical stress and the lack of a fundamental bond that contributes to the spatial organization of the cells. This status further induces possible alteration in cell metabolism and in gene expression. Unexpectedly, despite their fundamental involvement in the regulation of gene expression and their responsiveness to stresses, epigenetics modifications have been poorly studied in space and in altered gravityAltered gravity environment. Epigenetic modifications, such as DNA methylation, histones modifications, chromatin remodeling, and non-coding RNAs, can exert the role of mediator of the specific environmental stimuli encountered in space, resulting in modulations of the epigenome, possibly leading to altered cell response. Increasing evidence point out that this three-way interaction—environment–epigenome–cell—is associated to cell and tissue dyshomeostasis and possibly to disease onset. For this reason, increasing attention to the epigenetic modifications induced by the spatial environment and more comprehensive epigenetic studies are warranted. Unfortunately, the study of the epigenetic modifications in space presents some technical difficulty mainly due to the lability of some of these marks, particularly the most studied, i.e., the DNA methylation. Profiling the epigenetic modification often requires long and complex protocols that implies the use of specific instruments. These studies can be, on the other hand, performed on biological specimens collected during the space missions and returned to hearth. For the most labile epigenetic marks, using simulated microgravity on ground may represent a valid alternative approach. This chapter is therefore aimed at introducing the basics of the epigenetic modifications, the already known epigenetic changes associated to the space environment and the techniques used to study these marks.