The purpose of this review is to discuss recent developments in the biology and biochemistry of the T cells in mice and humans with systemic lupus erythematosus. T cells that recognize self-antigens are present in systemic lupus erythematosus and normal organisms. It is obvious, though, that an autoimmune environment should be present to disrupt anergy and instigate a response that might cause disease. The environment that lifts anergy is defined by distinct molecular aberrations that include rewiring of the T cells. Aberrant transcription of genes that encode proteins involved in autoimmunity can be traced to abnormal expression and activation of transcription factors and promoter methylation intensity. Only certain components of the autoimmune response can be linked to pathologic changes in the target organ that might be dictated by additional local factors. The works reviewed imply that self-peptides might be considered to reestablish lost tolerance, whereas correction of the aberrant biochemistry might normalize T cell function and limit disease.