The insulin and insulin like growth factor (IGF) signaling systems are implicated in breast cancer biology. Thus, disrupting IGF/insulin signaling has been shown to have promise in a number of preclinical models. However, human clinical trials have been less promising. Despite evidence of some activity in early phase trials, randomized phase III studies have thus far been unable to show a benefit of blocking IGF signaling in combination with conventional strategies. In breast cancer, combination anti IGF/insulin signaling agents with hormone therapy has not yet proven to have benefit. This inability to translate the preclinical findings into useful clinical strategies calls attention to the need for a deeper understanding of this complex pathway. Development of predictive biomarkers and optimal inhibitory strategies of the IGF/insulin system should yield better clinical strategies. Furthermore, unraveling the interaction between the IGF/insulin pathway and other critical signaling pathways in breast cancer biology, namely estrogen receptor-α (ERα) and epidermal growth factor receptor (EGFR) pathways, provides additional new concepts in designing combination therapies. In this review, we will briefly summarize the current strategies targeting the IGF/insulin system, discuss the possible reasons of success or failure of the existing therapies, and provide potential future directions for research and clinical trials.