A growing number of studies have revealed that the expression of many genes is abnormal in T lymphocytes of patients with systemic lupus erythematosus (SLE). Although aberrant expression of signaling molecules may arise intrinsically or in response to the environment, these abnormalities play a significant role in the pathogenesis of this autoimmune disease. Modern research on lymphocyte signaling abnormalities in SLE has been directed toward identifying defective expression of various signaling molecules, understanding the molecular basis of the deficiency, and dissecting the T-cell signaling abnormalities that result from abnormal gene expression. The developments suggest that interplay of abnormal transcriptional factor, aberrant messenger RNA processing/editing, ubiquitination, proteolysis, oxidative stress, and changes in chromatin structure invariably contribute to the abnormal expression of numerous signaling molecules in SLE T cells. The contribution of each of these mechanisms in the abnormal expression of signaling molecules in SLE T cells is not known. In addition to abnormalities in gene expression, multiple factors, including altered cellular distribution of the protein, rewiring of the receptor, modulation of membrane clustering, and lipid raft distribution of signaling molecules and defective signal-silencing mechanisms play a key role in delivering the anomalous T-cell receptor/CD3-mediated intracellular calcium response in SLE T cells. The optimized methods and protocols described here pertaining to TCR ζ-chain expression and related T-cell signaling abnormalities can be very well applied to other molecules aberrantly expressed in SLE T cells.