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Targeted nanoparticles have the potential to improve drug delivery efficiencies by more than two orders of magnitude, from the ~ 0.1% which is common today. Most pharmacologically agents on the market today are small drug molecules, which diffuse across the body’s blood-tissue barriers and distribute not only into the lesion, but into almost all organs. Drug actions in the non-lesion organs are an inescapable part of the drug delivery principle, causing “side-effects” which limit the maximally tolerable doses and result in inadequate therapy of many lesions. Nanoparticles only cross barriers by design, so side-effects are not built into their mode of operation. Delivery rates of almost 90% have been reported. This review examines the significance of these statements and checks how far they need qualification. What type of targeting is required? Is a single targeting sufficient? What new types of clinical challenge, such as immunogenicity, might attend the use of targeted nanoparticles?