Nanoparticles can provide effective control of the release rate and tissue distribution of their drug payload, leading to major pharmacokinetic and pharmacodynamic changes vis-à-vis the conventional administration of free drugs. In the last two decades, we have witnessed major progress in the synthesis and characterization of engineered nanoparticles for imaging and treatment of cancers, resulting in the approval for clinical use of several products and in new and promising approaches. Despite these advances, clinical applications of nanoparticle-based therapeutic and imaging agents remain limited due to biological, immunological, and translational barriers. There is a need to make high impact advances toward translation. In this review, we address biological, toxicological, immunological, and translational aspects of nanomedicine and discuss approaches to move the field forward productively. Overcoming these barriers may dramatically improve the development potential and role of nanomedicines in the oncology field and help meet the high expectations.