Nanomedicine for cancer, where nanoparticles (NPs) are used to deliver drugs, imaging agents, and heat to tumors, shows great potential of improved therapeutic outcomes. In spite of promising early stage results, its clinical efficacy is still significantly limited due to complex transport barriers in vivo. These transport barriers are associated with tumor microenvironment, which is highly complex and heterogeneous and varies spatiotemporally. Thus, in order to improve the in vivo efficacy of nanomedicine, NPs need to be designed and characterized considering their interaction with these complex transport barriers. In this article, thus, we discuss the multifaceted transport characteristics of NPs and their interaction mechanisms with the tumor microenvironment. We also illustrated that NPs have highly spatiotemporal and multiscale distribution around tumor. This dynamic and complex nature of NP transport needs to be taken into consideration in design strategies and evaluation criteria for successful delivery of cancer nanomedicine.