One explanation for the discordant response of agents that treat complications in rodents versus humans is that deleterious pathways that are responsive to a certain drug may be widely expressed in inbred animal models, but expressed in only a small number of individuals. Should some agents be tested in primates or some other larger mammal? Pharmacogenomic, pharmacometabolomic, and pharmacoproteomic approaches could be used to identify markers for people who would be responsive to specific agents, such as the case for haptoglobin genotypes and responses to vitamin E therapy. In addition, genotyping of individuals participating in clinical trials through networks such as the DRCR.net can provide information on the relationship between a genetic profile and the likely response to a particular therapy. Individually-tailored therapy for DN is a goal with enormous public health and patient benefit. Do dietary maneuvers or treatments that prevent the development of DN also prevent the progression of DN? What is the impact of diabetes duration and pre-existing tissue damage on the ability to respond to therapies? What behavioral interventions improve nutrition, diabetes adherence and self-management, and prevent DN? Will combination therapies be more effective than single therapies? Can mechanisms for efficient testing combination therapies be developed? What approaches will lead to individualizing therapies? Should therapies be targeted to specific tissues or should systemic therapies be emphasized?