Despite increases in screening and advances in treatment, breast cancer continues to be the most common cancer and cause of cancer deaths among women worldwide, and breast cancer rates have remained steady for decades. A new focus on population-level primary prevention is needed to tackle this disease at the most fundamental level. Unfortunately, only a small fraction of breast cancer research funds currently go to prevention. The California Breast Cancer Research Program (CBCRP) seeks to change this. In order to accelerate breast cancer primary prevention efforts, in 2018, CBCRP launched the Global Challenge to Prevent Breast Cancer, a prize competition to foster and disseminate new and innovative prevention research ideas. This Special Issue highlights the results of the Global Challenge and other CBCRP primary prevention efforts.