Pain is a disruptive influence on infants in the NICU. The most obvious and effective strategy to decrease infant pain in the NICU is to stringently limit the frequency of painful procedures, especially those that are most commonly reported (i.e., heel lances and endotracheal suctioning), and have these performed on infants that are most unstable or critically ill by the most experienced person available. Organizational concerns over the cost of NICU care have forced a re-evaluation of the necessity of certain diagnostic and care procedures and a limiting of procedures to those that can be documented to positively affect clinical outcome. Pharmacologic and nonpharmacologic strategies are essential to the prevention and management of neonatal pain, and these should be considered for complementary use for every infant. Research has shown the safety and effectiveness of some of the strategies in reducing mild pain caused by brief invasive procedures; however, many of the studies had methodologic limitations. Therefore, more research is required to determine the comparative efficacy of the various strategies and to document additive or synergistic effects when combined.