The O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status is the main biomarker to foresee GBM responsiveness to TMZ, but its predictive value is limited and additional functions of TMZ unrelated to MGMT activity are likely to underlie a further distinction between responders and non-responders due to specific features. The gene discussed is MGMT; the disease is glioblastoma.