Intentional delivery of high doses of nanoparticle-based drugs or diagnostic/imaging systems sets a new scenario in safety evaluation, compared with the environmentally borne unintentional exposure to engineered nanoparticles. Intravenously administered nanomedicines immediately interact with blood components such as serum proteins, changing their own characteristics and consequently the features of their interaction with cells and tissues. Of major importance is the interaction of nanomedicines with the immune system, which is essential in the recognition and elimination of foreign dangerous agents. Nanomedicines need to avoid immune recognition in order to reach their therapeutic target and display their effect, should not trigger defensive mechanisms that can damage the body tissues (e.g., complement activation or inflammation) and should not interfere with immunocompetent cells in order to avoid promoting immune-related diseases. This review will briefly cover these issues, and propose some knowledge-based approaches for future ‘safe-by-design’ nanomedicines.