This article highlights and discusses our experience in the design, handling, and biological evaluation of long-circulating nanoparticles based on polyoxypropylene/polyoxyethylene copolymer nonionic surfactants. A frequently observed but ignored phenomenon following intravenous injection of such polymer-modified long-circulating colloidal systems is their eventual recognition and clearance by macrophages of the reticuloendothelial system. The pharmacokinetics as well as the tissue distribution of such so-called 'stealth" nanoparticles are also altered after repeated intravenous injection in a time-dependent manner. An understanding of immunological and pathological factors that control the pharmacokinetic and biological behavior of long-circulating particles after single or repeated administration is therefore crucial for the design of a system with an optimal diagnostic and/or therapeutic performance. Therefore, we have also examined and discussed the concept of macrophage recognition of a 'stealth-like nature" and factors that initiate this cascade. A critical discussion of the future of this interesting area of nano-biotechnology/engineering is also provided.