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Advanced research in the field of cancer biology clearly demonstrated the key role of tumor microenvironment (TME) in cancer development and metastasis particularly in solid tumors. Components of TME, being non-neoplastic in nature provide supportive and permissive conditions for the growth of cancer cells. Hence it is important to modify TME in cancer therapy and this would be achieved by better understanding of TME morphological features and functioning of stromal components. Nanotechnology based drug delivery offers various advantages such as prolonged circulation time, delivery of cargo at desired site, improved bioavailability, reduced toxicity etc. over conventional chemotherapeutics. Abnormal characteristic features of TME play a paradoxical role in nanoparticulate drug delivery. Leaky vasculature, acidic and hypoxic conditions of TME helps in the accumulation of tailored nanoparticles whereas high interstitial pressure and dense stroma restrict the extravasation, homogenous distribution of nanocarriers in TME. This review mainly discusses the potential of nanotherapeutics in targeting TME by briefly discussing stromal components, therapeutic opportunities and barriers offered by TME for nanoparticulate drug delivery. Updated information on TME remodeling strategies for improved drug delivery and specific targeting of individual stromal components are also outlined.