The neonate receiving parenteral nutrition (PN) therapy requires a physiologically appropriate solution in quantity and quality given according to a timely, cost-effective strategy. Maintaining tissue integrity, metabolism, and growth in a neonate is challenging. To support infant growth and influence subsequent development requires critical timing for nutrition assessment and intervention. Providing amino acids to neonates has been shown to improve nitrogen balance, glucose metabolism, and amino acid profiles. In contrast, supplying the lipid emulsions (currently available in the United States) to provide essential fatty acids is not the optimal composition to help attenuate inflammation. Recent investigations with an omega-3 fish oil IV emulsion are promising, but there is need for further research and development. Complications from PN, however, remain problematic and include infection, hepatic dysfunction, and cholestasis. These complications in the neonate can affect morbidity and mortality, thus emphasizing the preference to provide early enteral feedings, as well as medication therapy to improve liver health and outcome. Potential strategies aimed at enhancing PN therapy in the neonate are highlighted in this review, and a summary of guidelines for practical management is included.