The current path to drug approval in early breast cancer takes too long, especially impacting high-risk patients with potential cure. The recent guidance issued by the FDA to the industry is a major step forward. However, there are several issues that still need to be resolved and these are being actively discussed in multiple forums. The challenges in design and implementation of early trials to support registration for Early Breast Cancer will be discussed. The intricacies of ‘single-trial’ versus ‘multiple-trials’ approaches and the impact of later therapies in establishing long-term benefit of neo-adjuvant treatments in clinical trials will be discussed