Modification by SUMOs (small ubiquitin-related modifiers) is largely transient and considered to alter protein function through altered protein-protein interactions. These modifications are significant regulators of the response to DNA damage in eukaryotic model organisms and SUMOylation affects a large number of proteins in mammalian cells, including several proteins involved in the response to genomic lesions [Golebiowski, Matic, Tatham, Cole, Yin, Nakamura, Cox, Barton, Mann and Hay (2009) Sci. Signaling 2, ra24]. Furthermore, recent work [Morris, Boutell, Keppler, Densham, Weekes, Alamshah, Butler, Galanty, Pangon, Kiuchi, Ng and Solomon (2009) Nature 462, 886-890; Galanty, Belotserkovskaya, Coates, Polo, Miller and Jackson (2009) Nature 462, 935-939] has revealed the involvement of the SUMO cascade in the BRCA1 (breast-cancer susceptibility gene 1) pathway response after DNA damage. The present review examines roles described for the SUMO pathway in the way mammalian cells respond to genotoxic stress.