Specific small-molecule inhibitors of MEK are promising anticancer agents targeting the oncogenic RAF-MEK-ERK pathway. Breast cancer, as in most solid malignancies, is a phenotypically and molecularly heterogeneous disease. It is unclear whether individual breast cancer subtypes are particularly susceptible to these agents. Mirzoeva and colleagues used a systems-based approach to identify such subtypes and to understand molecular mechanisms conferring resistance to MEK inhibitors. Basal-type breast cancer cells were found to be particularly susceptible to growth-inhibition by small-molecule inhibitors. The cover image demonstrates results of an mRNA expression array analysis of MEK-related gene predictors of response to MEK inhibitors. Genes in the upper panel predict sensitivity to MEK inhibitors, whereas those in the lower panel predict resistance. In the tree, yellow end-nodes denote basal-type cell lines and pink end-nodes denote luminal cell lines. These data, in conjunction with the additional finding of interconnectivity between the MEK and PI3 kinase signal transduction pathways, have implications for future clinical trials of MEK inhibitors and also suggest rationally designed combination therapies. For details, see the article by Mirzoeva and colleagues on page 565 of this issue.