The emergence of influenza drug resistance is a major public health concern. The molecular basis of resistance to oseltamivir (Tamiflu) is investigated using a computational assay involving multiple 500 ns unrestrained molecular dynamics (MD) simulations of oseltamivir complexed with mutants of H1N1-2009 influenza neuraminidase. The simulations, accelerated using graphics processors (GPUs), and using a fully explicit model of water, are of sufficient length to observe multiple drug unbinding and rebinding events. Drug unbinding occurs during simulations of known oseltamivir-resistant mutants of neuraminidase. Molecular-level rationalisations of drug resistance are revealed by analysis of these unbinding trajectories, with particular emphasis on the dynamics of the mutant residues. The results indicate that MD simulations can predict weakening of binding associated with drug resistance. In addition, visualisation and analysis of binding site water molecules reveals their importance in stabilising the binding mode of the drug. Drug unbinding is accompanied by conformational changes, driven by the mutant residues, that results in flooding of a key pocket containing tightly bound water molecules. This displaces oseltamivir, allowing the tightly bound water molecules to be released into bulk. In addition to the role of water, analysis of the trajectories reveals novel behavior of the structurally-important 150-loop. Motion of the loop, which can move between an open and closed conformation, is intimately associated with drug unbinding and rebinding. Opening of the loop occurs co-incidentally with drug unbinding, and interactions between oseltamivir and the loop seem to aid in the repositioning of the drug back into an approximation of its original binding mode on rebinding. The similarity of oseltamivir to a transition state analog for neuraminidase suggests that the dynamics of the loop could play an important functional role in the enzyme, with loop closing aiding in binding of the substrate, and loop opening aiding the release of the product.