The Patient Protection and Affordable Care Act is motivated by the imperative to reduce the continuous growth in healthcare spending, as the rapid rise in healthcare spending has become a threat to the economic future of the United States. Nurse practitioners have the potential to lower costs by assuming provider roles within the healthcare workforce to deliver care of equal or better quality at lower costs than comparable services by other providers. The published literature was reviewed to assess the cost-effectiveness of care provided by nurse practitioners as compared to physicians in a wide variety of primary and acute care clinical settings. Cost-effectiveness analysis from payer, societal, and hospital and employer stakeholder perspectives supports the substitution of nurse practitioners for physicians in their overlapping scopes of practice, as nurse practitioners provide cost-effective care in primary and acute care settings.