The propensity of the hepatic macrophages (Kupffer cells) to rapidly intercept particulate materials from the blood has been frustrating in redirecting intravenously injected nanomedicines to pathological sites in sufficient quantities to exert appropriate pharmacological effect. The development of long circulating nanoparticles has offered unprecedented opportunities for controlled drug release within vasculature and for drug delivery to sites other than Kupffer cells. These developments were based on mechanistic understanding of complex and integrated body’s defences against intruders as well as translation of protective strategies developed by the body’s own cells and virulent pathogens against immune attack. Thanks to interdisciplinary and integrated approaches, numerous organic and inorganic nanoparticles with long circulating properties have become available. By long circulation we mean particles that remain in the blood for periods of hours rather than minutes, but blood longevity must be tuned in accordance with therapeutic needs. Here, we provide a brief history of these efforts and highlight important lessons learned in camouflaging nanoparticles with strategies that avoid rapid interception by Kupffer cells.