The quartz crystal microbalance (QCM) is a highly sensitive instrument which determines the nature of binding interactions in real time within a label free environment. Current advances in this technology have afforded increased stability, sensitivity, parallel control availability, high throughput capacity and an increased range of experimental configurations. QCM is ideally suited to the study of nanomedicine where investigation of nanovehicle performance in the biological milieu has become of increased clinical significance. Primary issues include activation of the complement system and induction of apoptosis. It is the aim of this review to discuss the opportunities afforded by the QCM in the mechanistic understanding of interaction in the biological environment and how this can be applied to improved nanoconstruct design to attain performance enhancement.