A promising strategy to improve health is the rational manipulation of one's beneficial microbiota via dietary interventions. This is observed in nature where specific bifidobacteria utilize human milk oligosaccharides (HMOs) that are encountered within the breast-fed infant colon. Bifidobacterium longum subsp. infantis is regarded as the archetypical HMO consumer associated with the developing neonate. This review summarizes the known molecular mechanisms underlying HMO utilization, as determined for bifidobacterial commensals. In addition, future directions of HMO research are discussed with an emphasis on physiological, ecological and clinical approaches to understand bifidobacterial utilization of this intriguing substrate.