We identify and describe nine key, short-term, challenges to help healthcare organizations, health information technology developers, researchers, policymakers, and funders focus their efforts on health information technology-related patient safety. Categorized according to the stage of the health information technology lifecycle where they appear, these challenges relate to (1) developing models, methods, and tools to enable risk assessment; (2) developing standard user interface design features and functions; (3) ensuring the safety of software in an interfaced, network-enabled clinical environment; (4) implementing a method for unambiguous patient identification (1-4 Design and Development stage); (5) developing and implementing decision support which improves safety; (6) identifying practices to safely manage information technology system transitions (5 and 6 Implementation and Use stage); (7) developing real-time methods to enable automated surveillance and monitoring of system performance and safety; (8) establishing the cultural and legal framework/safe harbor to allow sharing information about hazards and adverse events; and (9) developing models and methods for consumers/patients to improve health information technology safety (7-9 Monitoring, Evaluation, and Optimization stage). These challenges represent key “to-do’s” that must be completed before we can expect to have safe, reliable, and efficient health information technology-based systems required to care for patients.