Parenteral nutrition (PN), containing fat emulsions derived from soybean, has been implicated in the progression of PN-associated liver disease and cholestasis, particularly in infants with short bowel syndrome. Clinical use of Omegaven, a parenteral fish-oil emulsion, has been shown in recent studies to be a promising therapy to reverse liver disease and cholestasis. This review summarizes the rationale, relevant clinical investigations and future direction of Omegaven therapy for PN-dependent infants.