Activation of oncogenes and inactivation of tumour suppressor genes are common events during breast cancer initiation and progression and often determine treatment responsiveness. Indeed, these events need to be recreated in in vitro systems and in mouse cancer models in order to unravel the molecular mechanisms involved in breast cancer initiation and metastasis and assess their possible impact on responses to anticancer drugs. Optical-based imaging models are used to investigate and to follow important tumour progression processes. Moreover, the development of novel anticancer strategies requires more sensitive and less invasive methods to detect and monitor in vivo drug responses in breast cancer models. This review highlights some of the current strategies for modelling breast cancer in vitro and in the mouse, in order to answer biological or translational questions about human breast malignancies.