The Mononuclear Phagocyte System (MPS) is a major constraint to nanocarrier-based drug-delivery systems (DDS) by exerting a negative impact on blood circulation times and biodistribution. Current approaches rely on the protein-and cell-repelling properties of inert hydrophilic polymers, to enable escape from the MPS. Poly(ethylene glycol) (PEG) has been particularly useful in this regard, and it also exerts positive effects in other blood compatibility parameters, being correlated with decreased hemolysis, thrombogenicity, complement activation and protein adsorption, due to its uncharged and hydrophilic nature. However, PEGylated nanocarriers are commonly found in the liver and spleen, the major MPS organs. In fact, a hydrophilic and cell-repelling delivery system is not always beneficial, as it might decrease the interaction with the target cell and hinder drug release. Here, a full scope of the immunological and biochemical barriers is presented along with some selected examples of alternatives to PEGylation. We present a novel conceptual approach that includes virulence factors for the engineering of bioactive, immune system-evasive stealth nanocarriers. From the Clinical Editor: The efficacy of nanocarrier-based drug-delivery systems is often dampened by the Mononuclear Phagocyte System (MPS). Current approaches to circumvent MPS rely on protein-and cell-repelling properties of inert hydrophilic polymers, including PEG. This paper discusses the full scope of the immunological and biochemical barriers along with selected examples of alternatives to PEGylation. (C) 2011 Elsevier Inc. All rights reserved.