Visceral pain in infants represents a complexity of interacting neural, developmental, psychosocial, and environmental factors, which must be separately and conjointly evaluated. Inhibitory mechanisms are not fully developed in infants and thus nociception is not readily dampened. Heightened behavioral responses to pain (e.g., crying) are likewise not easily inhibited. Esophageal pain and behaviors perceived by the caregiver to represent pain (e.g., crying and retching) can potentially affect normal growth and development. The response of the infant to pain and other visceral sensory stimuli and the ability to cope with these sensations (painful and nonpainful) are shaped by the relationship of the infant with the primary caregiver, usually the mother. Neural mechanisms of pain transmission and inhibition are reviewed, as well as biopsychosocial and environmental characteristics that can shape or contribute to infant pain syndromes. Proposed multifaceted clinical treatment strategies are aimed at decreasing efforts to dampen excitatory neural sensory signaling and improving the mother/infant relationship and maternal behavioral response to the crying infant.