Abstract In the January 1, 2017, issue of Cancer Research, Nagel and colleagues demonstrate the value of assays that determine the DNA repair capacity of cancers in predicting response to temozolomide. Using a fluorescence-based multiplex flow cytometric host cell reactivation assay that provides simultaneous readout of DNA repair capacity across multiple pathways, they show that the multivariate drug response models derived from cell line data were applicable to patient-derived xenograft models of glioblastoma. In this commentary, we first outline the mechanism of activity and current clinical application of temozolomide, which, until now, has been largely limited to glioblastoma. Given the challenges of clinical application of functional assays, we argue that functional readouts be approximated by genomic signatures. In this context, a combination of MGMT activity and mismatch repair (MMR) status of the tumor are important parameters that determine sensitivity to temozolomide. More reliable methods are needed to determine MGMT activity as DNA methylation, the current standard, does not accurately reflect the expression of MGMT. Also, genomics for MMR are warranted. Furthermore, based on patterns of MGMT expression across different solid tumors, we make a case for revisiting temozolomide use in a broader spectrum of cancers based on our current understanding of its molecular basis of activity. Cancer Res; 77(4); 823–6. ©2017 AACR.