The success of targeted therapies in treating cancer over the last decade has been tempered by acquired drug resistance that follows long-term treatment. There is also emerging evidence for innate mechanisms of cancer cell resistance to targeted therapy that pre-exist as parallel signalling pathways. This aspect is explored by the Alessi group and collaborators from AstraZeneca in this issue of the Biochemical Journal, who identify a subset of breast cancer cell lines that are intrinsically resistant to Akt inhibition through constitutive up-regulation of the related AGC serine/threonine kinase SGK1 (serum- and glucocorticoid-regulated kinase 1). The study could help to profile tumours for sensitivity to Akt inhibitors and once more highlights the therapeutic complexity of cancer and the importance of exploring combination therapies in the clinic.