Environmental factors are capable of triggering the expression of human endogenous retroviruses and induce an autoimmune response. Infection can promote the expression of human endogenous retroviruses by molecular mimicry or by functional mimicry. There are additional mechanisms which may control the expression of human endogenous retroviruses, such as epigenetic status of the genome (hypomethylation, histone deacetylation). Ultraviolet exposure, chemicals/drugs, injury/stress, hormones, all as a single cause or in a concert, may modulate the involvement of human endogenous retroviruses in pathogenic processes. In the current review we summarize the current knowledge on infections, molecular mimicry, cross-reactivity and epigenetics contribution for trigger human endogenous retroviruses expression and pathogenesis in lupus patients.