The interface of bio-nano science and cancer medicine is an area experiencing much progress but also beset with controversy. Core concepts of the field-e.g., the enhanced permeability and retention (EPR) effect, tumor targeting and accumulation, and even the purpose of "nano" in cancer medicine-are hotly debated. In parallel, considerable advances in neighboring fields are occurring rapidly, including the recent progress of "immuno-oncology" and the fundamental impact it is having on our understanding and the clinical treatment of the group of diseases collectively known as cancer. Herein, we (i) revisit how cancer is commonly treated in the clinic and how this relates to nanomedicine; (ii) examine the ongoing debate on the relevance of the EPR effect and tumor targeting; (iii) highlight ways to improve the next-generation of nanomedicines; and (iv) discuss the emerging concept of working with (and not against) biology. While discussing these controversies, challenges, emerging concepts, and opportunities, we explore new directions for the field of cancer nanomedicine.