Advanced estrogen receptor positive (ER+) breast cancer is responsible for more than 50% of breast cancer deaths. CDK4/6 inhibitors, such as Ribociclib, have been the most effective drugs to be released for ER+ patients in the last 10 years. They double survival, are orally administered, and have few side effects. But we have no way to treat patients once their cancer becomes resistant to CDK4/6 inhibitors and the cancer recurs. A personalised medicine approach to improve drug targeting in this setting is therefore critical. Using cutting-edge imaging technology and 3D patient-derived models that mimic the disease, we can map areas of poor drug response within distinct regions of tumours. Here, we will counteract factors driving drug resistance in these areas.