Accumulating epidemiological, clinical, and experimental evidence supports the conclusion of a critical role of epigenetic factors in immune programming. This understanding provides the basis for elucidating how the intricate interactions of the genome, epigenome, and transcriptome shape immune responses and maintain immune tolerance to self-antigens. Deciphering the precise contribution of epigenetic factors to autoimmunity, and in particular to lupus, has become an active research area. On one hand, it is well established that environmental factors have an impact on the epigenome and, therefore, on the transcriptional and translational machinery of specific cell types; on the other, the environment also plays an important role in the severity of lupus and other autoimmunity diseases. Determining how epigenetics "connects" the environment to cell biology and to autoreactivity will be key for advancing our understanding in this field and, possibly, for developing novel preventive strategies.