Obesity is a risk factor associated with increased cancer growth, progression and decreased efficacy of anti-cancer drugs. Our group has recently shown that adipocytes promote breast cancer cell proliferation and migration using both co-culture and conditioned media approaches. In this study, we hypothesised that adipocytes compromise anti-cancer treatments. Indeed, we found that introduction of adipocyte conditioned media (CM) decreased the growth inhibitory effects of anti-cancer therapies including cyclophosphamide, docetaxel, doxorubicin, paclitaxel and tamoxifen in estrogen-receptor positive MCF-7 cells. Interestingly, as most of these anti-cancer drugs are pro-drugs, introduction of adipocyte CM to cells 24 h (paclitaxel, doxorubicin) or 72 h (cyclophosphamide) after administration of anti-cancer drugs had a more striking effect on reducing the growth inhibitory effects of anti-cancer therapies. Interestingly, most anti-cancer drugs, except paclitaxel, increased MCF-7 triacylglycerol levels following 24 h of administration. Cyclophosphamide-stimulated increase in MCF-7 triacylglycerol levels was due to increased fatty acid uptake and not de novo lipogenesis. The adipocyte-induced reduction in the efficacy of cyclophosphamide to inhibit growth was not associated with changes in fatty acid metabolism. These results demonstrate that adipocytes have an ability to release factors that diminish the efficacy of anti-cancer agents and that anti-cancer drugs alter MCF-7 fatty acid metabolism. Collectively, these observations may have significant implications for current therapies in patients with expanded adipose tissues.