Nanocarriers with unique characteristics have attracted great attentions in tumor treatment, but therapeutic efficacy of drugs is limited by the nonuniform delivery of nanocarriers to tumor by three progresses blood circulation system, tumor vessels and tumor interstitium. The total number of nanocarriers usually was reduced dramatically into tumor, because nanocarriers in blood vessels always can be cleared by RES system or accumulated in kidney and liver. Abnormal vessels are almost uneven allocation on tumor surface and cannot contribute to deliver nanocarriers to all the region of tumors, especially the interior of tumors. In addition, nanocarriers will be retained in perivascular space of tumor under high interstitial fluid pressure (IFP) and heterogeneous structure of tumor matrix. In this article, we reviewed the structure of nanocarriers and the barriers in tumor microenvironment influencing delivery of nanocarriers. With the aim of transport over these barriers to increase the delivery efficiency of nanocarriers, two strategies tumor microenvironment normalization and nanocarriers optimization were proposed and designed. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 101A: 3661–3669, 2013.