By using the body’s own immune response, immunotherapy is proving to be a turning point in the treatment of cancer. It has yielded exciting and durable remissions across a spectrum of malignancies, particularly melanoma and non-small cell lung cancer. Notwithstanding these encouraging signs, predictors of a patient’s response to immunotherapy remain to be defined, as actual responses are heterogeneous and difficult to study in real-time. The important question is: what is behind the success or failure of immunotherapy? And is it possible to stratify responders from nonresponders early after the start of therapy? To tackle this issue, we need new methods to non-invasively explore the microenvironment of tumors and to enumerate the relevant cell types. Because the drugs are toxic, the ability to monitor the immune response throughout the course of therapy will enable an early determination of the efficacy of the intervention, and inform decisions as to whether treatment should be stopped or continued. Non-invasive monitoring could therefore change how therapies are applied and assessed, to the benefit of many patients.