Epigenetic modulation has become of increasing interest for our understanding of the regulation of not only developmental programming, but also the modulation of cellular responses to environmental interaction. Epigenetic modification arises through changes in DNA methylation status or histone modification, without alteration of the nucleotide sequence within the genome. These changes may either be assessed in terms of global changes or as gene-specific modifications. The tools available for assessment of epigenetic modifications are becoming more and more advanced and are continuously opening new avenues for investigation in this field. Recently, it has been suggested that the epigenome could potentially be manipulated to achieve therapeutic effects in a variety of disease states – this notion of controlled gene-specific epigenetic editing for therapeutic purposes will be revisited. An interesting aspect of epigenetic modification in response to environmental conditioning is the question of the stability of these resulting effects. Here, the capacity for transgenerational transfer of these modifications will be discussed, in the context of nutrition, stress and diabetes. With this talk, our particular focus will be on obesity and the related inflammatory state, as well as effects of exercise. The rising prevalence of obesity globally is linked to concurrent increases in inflammatory diseases as well as pathologies with inflammation as an aetiological factor. Epigenetic mechanisms have been proposed to be the cause of this inflammatory state observed in obesity. In mouse adipocytes for example, overexpression of DNMT3A resulted in increased expression of pro-inflammatory genes in obese mice. Similarly, epigenetic modifications have also been illustrated in models of dietary obesity. In this context, rats fed a high energy diet had significantly higher methylation in the leptin gene promotor region, which was associated with lower circulating leptin levels. At least some of the epigenetic modifications associated with dietary obesity-related inflammation is transgenerationally transferred – an upregulation of NLRC4, which is critical in the formation of the inflammasome, was reported in both first and second generation offspring in high-fat fed mice. From the studies reviewed, excessive inflammatory states seem to result from DNA hypomethylation, which leads to an upregulation of inflammatory gene expression. This poses an interesting question: are high-performance athletes at risk of inflammation-induced epigenetic modification? Although results from human studies in the context of habitual exercise are emerging to inform on the effect of exercise on the epigenome, the models used and focus parameters are quite varied, so that we have more questions than answers at this stage. The burning issues in the field will be highlighted. Finally, some interesting recent findings on IL-6 signalling from separate human exercise studies performed in our own and collaborator laboratories will be discussed in terms of modifications at both protein expression and epigenetic level, in an attempt to answer this question.