Discrete pathologies have unique features that contribute to disease progression. Each lesion contains unique clusters of cells and other factors that make up specific micro-niches. Individual microniches present novel barriers that hamper the delivery of therapeutics, but it also contains characteristic elements that can favour accumulation of therapeutics within the lesion. This chapter discusses the unique biology associated with cancer, cardiovascular disease, and neurological disorders and describes how each unique presentation can be used to optimize nanoparticle design for targeting the lesion.