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Patient safety is one of the greatest imperatives in healthcare today, yet there are many obstacles that must be overcome to make healthcare delivery truly safe. Critically ill newborns are among the most medically fragile patients in hospitals today. Given their size and gestational age, the tolerance for error within this population is extremely small. Medical errors that may be less consequential in adults can be disastrous for infants. Developing a culture of safety demands a mind-set that continuously seeks out vulnerabilities and prospectively addresses them through systems-based rather than individual-based solutions. The complexities of clinical care and intricacies of human behavior may prevent total elimination of risk, but caregivers are in a position to develop a culture of safety that can minimize risks for adverse events in the neonatal intensive care unit. Specific strategies used to successfully implement a staff-focused patient safety program are described in this article. These strategies include the development of systemwide and unit-based interdisciplinary safety teams to proactively identify and address safety concerns, development of specific tools and techniques used for analysis and prioritization of risk, resources that teams used to support an environment of safety; and implementation of staff-driven solutions to address safety concerns.