Parenteral nutrition (PN)-related bone disease remains a problem in patients of all ages. Understanding of the pathogenesis of PN-related bone disease is complicated by the effect of underlying illnesses, therapeutic interventions, and pre-existing nutrition deficiencies before the initiation of PN therapy. Interrelation of various nutrients, for example, calcium, phosphorus, and vitamin D, in their effects on bone mineralization, demands simultaneous assessment of the role of multiple nutrients and increases the difficulty in defining the role of a single nutrient in the development of bone disease. However, recent reports indicate that there exist a number of factors important in the development of PN-related bone disease and some factors such as increased mineral requirement are unique to growing infants whereas other factors such as aluminum toxicity may be common to both adult and pediatric populations. Nonnutritional factors, including chronic use of potent loop diuretics and altered acid-base status, can affect urine mineral loss, cell metabolism, and bone mineralization, particularly in small, preterm infants. Current evidence indicates that the cause of PN-related bone disease is multifactorial, and the prevention of PN-related bone disease awaits better delineation of the exact sequence of pathogenic events.