Epigenetic mechanisms are able to alter gene expression, without altering DNA sequence, in a stable manner through cell divisions. They include, among others, the methylation of DNA cytosines and microRNAs and allow the cells to adapt to changing environmental conditions. In recent years, epigenetic association studies are providing new insights into the pathogenesis of complex disorders including prevalent skeletal disorders. Unlike the genome, the epigenome is cell and tissue specific and may change with age and a number of acquired factors. This poses particular difficulties for the design and interpretation of epigenetic studies, particularly those exploring the association of genome-wide epigenetic marks with disease phenotypes. In this report, we propose a framework to help in the critical appraisal of epigenetic association studies. In line with previous suggestions, we focus on the questions critical to appraise the validity of the study, to interpret the results and to assess the generalizability and relevance of the information.