Nanoparticles have long been sought as promising drug delivery system for cancer therapy, including liposomes, polymeric micelles, polymer-drug conjugates, dendrimers and polymeric nanoparticles. However, conventional nanoparticles would be specifically entrapped by the monocyte phagocytic system (MPS), and then quickly eliminated following intravenous administration, so the applications of nanoparticles are limited due to short circulation lifetime. Since long-circulation property is the prerequisite for nanoparticles reaching the target site of interest, the nanoparticle surface is usually modified by hydrophilic polymer materials such as PEG, to reduce plasma opsonization and MPS uptake. Furthermore, increased tumor specificity and cell internalization will improve the treatment efficacy and decrease the serious side effects for many cytotoxic antineoplastic drugs. Introducing the targeting ligands for interaction with specific tumor cells or tissues will offer major enhancement in cancer therapeutics via site specificity, reduction of multidrug resistance and improved delivery efficiency. This article will give an overview on the current state of long-circulating nanoparticles and describe their major advantages and potential pitfalls. Special emphasis is placed on the superiority of long-circulating nanoparticles used for tumor targeting.