The phosphatidylinositol 3 OH-kinase (PI3K) pathway is a key intracellular signalling cascade in cellular survival. Our previous studies indicated that specific blockade of this enzyme led to sensitisation of human breast carcinoma cells to killing by doxorubicin through induction of both G2 arrest and apoptosis in some, but not all, breast cancer cells. In the present study, we report that inhibition of a down-stream component of this pathway, Akt, is an effective means of enhancing doxorubicin killing in some breast cell types. Doxorubicin (Dox) and six Akt inhibitors were used individually or in combination on MDA-MB-231 (p53 mutant, ER-), T47D (p53 mutant, ER+), and MCF-7 (p53 wt, ER+) human breast cancer cell lines. In MDA-MB-231 breast cancer cells, all six Akt inhibitors, which have differing mechanisms of action to inhibit Akt, synergised with the growth inhibitory effects of doxorubicin. Two Akt inhibitors also enhanced the effect of Dox in T47D cells but the other inhibitors induced additive effects in these cells. None of the inhibitors used elicited enhanced effects in MCF-7 cells. These results support the notion that combination therapies of doxorubicin (and possibly other chemotherapeutics) with inhibitors of elements of the PI3K pathway are a realistic possibility for future breast cancer therapy, which could lead to reduced side-effects, but that this could be dependent on the genetic background of each breast cancer.