This is a review of nanotherapeutic systems, specifically those that exhibit controlled release of the encapsulated bioactive compound. The survey includes the delivery of a range of bioactive compounds, from lipophilic small molecules to hydrophilic proteins and siRNA molecules. The research into enabling sustained delivery of these compounds from nanocarriers has been prolific, but clinical success has been harder to achieve. This is partly because achieving true sustained duration of action over several days is difficult when the carrier dimensions become less than about 400 nm, due to the much shorter diffusion path length compared to micron-sized carrier systems. Other options must be sought to control the efflux of incorporated bioactives, particularly when these bioactives have moderate to high hydrophilicity. A few of these options are discussed critically in this review. We also answer the question: is controlled release needed for nanotherapies? We present the case for controlled release in specific conditions, with two examples from our own work: one for treatment of glaucoma, and the second for inhibition of fibrosis following surgery. The former is sustaining the release of a small-molecule lipophilic drug, while the latter focusses on sustained siRNA delivery.