B y the time their child is 4 months old, up to 20% of parents have reported colicky symptoms in their infants. Is infant colic a disorder? Is it related to the intestine, as the term colic implies? Is any treatment other than reassurance of families regarding the transient nature of these symptoms indicated? In short, are we stepping in an evidence-based arena or are we dealing with ‘‘gut feelings’’? This supplement on infant crying, colic, and gastrointestinal (GI) disturbances in early childhood provides theoretical and clinical observations on this and other intriguing functional GI topics. The supplement provides the scientific and clinical evidence that should guide current clinical practice and serve future studies that will enable better understanding and appropriate management by physicians and families alike. Burns and Thapar review the embryonic and postnatal events related to the enteric nervous system (ENS), which is the regulator of gut secretion, blood flow, sensation, and coordinated motility (1). They provide evidence that a significant amount of modification of the ENS occurs not only during the fetal period but also postnatally; thus the ENS can be altered in a number of ways: stress, infections, and changes in nutrition. Indrio et al focus on the non-nutritive pathophysiology of colic, looking at the relation of colic to gastroesophageal reflux (GER), GI motility disorders, the role of gut hormones, and intestinal microflora (2). Their review raises the old debate of whether colic is a functional disorder (eg, troubling GER or ‘‘immature’’ motility) or should be regarded as a normal developmental occurrence. The authors correctly conclude that ‘‘little evidence supports a substantial role of GER or GERD in the majority of infants with colic,’’ and observations for the role of hormones such as ghrelin and motilin as well as the positive effect shown for probiotic supplementation should be studied further. Indrio and colleagues also elaborate on the role of probiotics in the management of infant colic and provide recent and exciting data on the clinical benefit of the administration of probiotics in treating functional disorders and organic diseases (3). This review explores the hypothesis that there is a window of time when the gut microbiota may affect the structure and the function of the brain. The review by Di Lorenzo on early life events brings us elegantly to the ‘‘vulnerable child,’’ summarizing what is known about factors that predispose an infant to become colicky (4). Much of the available data refers to the possible link among infectious, inflammatory, and psychological noxious events that may cause changes in enteric nerve reactivity, as well as immune responses or alterations in intestinal microbiota composition that can then lead to functional GI disorders later in life. For example, there is evidence that early pain experiences are associated with altered pain responses later in infancy. Although the genetic background cannot be changed and the stressful events may be unavoidable, identifying the child at risk may provide an opportunity for interventions that will attenuate or prevent later functional disorders. Ha-Vinh Leuchter et al discuss the possibility that the peak shape of the crying behavior found in colicky as opposed to noncolicky babies, the circadian rhythm of the crying, and the observation that these babies are not soothed by ordinary sensory stimulation reflect a difference in central nervous system functioning (eg, differences in circadian rhythm maturation, different response to stimuli) rather than GI dysfunction (5). Heine summarizes available data on the relation between cow’s-milk allergy and infant colic (6). He notes that in breast-fed infants, elimination of cow’s milk and other food proteins from the maternal diet was associated with a greater reduction in crying or fussiness duration, and that the treatment of formula-fed infants with extensively hydrolysed formula was associated with reduced crying in several clinical trials. The use of lactose-free formulae provides inconsistent results, however. A limited trial of an Infant Crying, Colic, and Gastrointestinal Discomfort in Early Childhood: A Review of the Evidence and Most Plausible Mechanisms