The way we view cancer has advanced greatly in the past few decades from simplistic approaches to finely honed systems. This transition has been made possible because of advancements on two fronts: the first is the rapidly expanding knowledge base of the mechanisms and characteristics of cancer; the second is innovation in imaging agent design. Rapid advancements in imaging and therapeutic agents are being made through the evolution from one-dimensional molecules to multi-functional nanoparticles. Powerful new agents that have high specificity and minimal toxicity are being developed for in vivo imaging. Here we detail the unique characteristics of cancer that allow differentiation from normal tissue and how they are exploited in nanoparticle imaging development. Firstly, genetic alterations, either endogenous or induced through gene therapy, are one such class of characteristics. Proteomic differences such as overexpressed surface receptors is another targetable feature used for enhanced nanoparticle retention. Increased need for nutrients and specific growth signals to sustain proliferation and angiogenesis are further examples of how cancer can be targeted. Lastly, migration and invasion through a unique microenvironment are two additional traits that are exploitable, due to differences in metalloproteinase concentrations and other factors. These differences are guiding current nanoparticle design to better target, image and treat cancer.