In preclinical model systems, the fundamental principles underlying a successful and durable anti-tumour immune response are well demonstrated. In clinical practice, significant successes in Phase III trials have been few over the last decades, but the field has gained tremendous interest following recent advances showing the activity of checkpoint blockade inhibitors. Still, at this time we do not fully understand why some people respond while others do not; nor do we completely understand which clinical and immunological monitoring tools we need to put in place to make immunotherapy a more controlled medical science. Reviewing recent evidence suggests that for a successful and controlled immunotherapy, we may need to juggle with several conditions at the same time; there is a need for the endogenous or exogenous addition of tumour antigens for a favourable tumour microenvironment, and for an immune system which remains actionable towards T cell (effector) activity by checkpoint blockade inhibitors.