The growing research interest in nanomedicine for the treatment of cancer and inflammatory-related pathologies is yielding encouraging results. Unfortunately, enthusiasm is tempered by the limited specificity of the enhanced permeability and retention effect. Factors such as lack of cellular specificity, low vascular density, and early release of active agents prior to reaching their target contribute to the limitations of the enhanced permeability and retention effect. However, improved nanomedicine designs are creating opportunities to overcome these problems. In this review, we present examples of the advances made in this field and endeavor to highlight the potential of these emerging technologies to improve targeting of nanomedicine to specific pathological cells and tissues.