The ability to predict the response to neoadjuvant chemotherapy (NAC) prior to or shortly after commencing treatment, in women with large or locally advanced breast cancers, would not only prevent patients from experiencing unnecessary drug morbidity but also reduce the high cost associated with drug usage and utilisation of resources with NAC. Ability to estimate residual cancer volume after NAC is of clinical relevance to subsequent therapeutic surgical options. Various approaches, using conventional histopathological characteristics and imaging modalities to evaluate and predict the response to NAC, have not been able to provide accurate and reliable data. Novel biomolecular imaging, new biomarkers and recent cancer genomic and proteomic profiling, introduced into clinical practice, have produced preliminary promising results. We describe and discuss these molecular characteristics and approaches and their applications to NAC in breast cancer management.