Excessive crying is the most common problem presenting to the doctor in the first months of life in western industrialised societies, affecting up to 30% of infants. There has been an exponential increase in the diagnosis of gastro-oesophageal reflux disease (GORD) in babies who cry excessively over the past few decades, and many parents believe their crying infant "has reflux". This paper proposes that culturocentric assumptions have confused interpretation of research into GORD, and re-examines the findings of GORD research from the perspective of evolutionary biology. Evolutionary biologists argue that the human infant is an exterogestate foetus for at least the first six months of life, dependent on maternal co-regulation for optimal physiological function. However, infant-care practices in western industrialised societies shifted towards an emphasis on infant autonomy at the time of the Industrial Revolution. From the perspective of evolutionary biology, a misalignment between western culture and the biological expectations of the infant developed over two million years of evolution may result in excessive crying in less adapted babies. The key biocultural factors that impact on infant distress are feeding management, parental responsiveness, sensory nourishment and sleep management. When the concept of the human infant as an exterogestate foetus is integrated with the findings of GORD research, a hypothesis and its corollary emerge. This hypothesis proposes that infant GORD is a physiological manifestation of misalignment between biology and culture, and proposes, as a corollary, that if the impact of biocultural factors upon the physiology of otherwise well crying babies is not addressed in the first months of life, populations of infants who cry excessively may be predisposed to GORD after three to four months of age. If this hypothesis is correct, an integrated clinical approach to crying babies less than three to four months of age that considers feeding management (e.g., frequent feeds, breast- or bottle-feeding technique, referral to a lactation consultant, cow's milk allergy), parental responsiveness (e.g., prompt response to infant cues), sensory nourishment (e.g., sling or backpack, walks, massage) and sleep management (e.g., nocturnal co-sleeping) should, firstly, decrease crying when applied to infants less than three to four months of age, and secondly, decrease the incidence of GORD in these infants once they are older than three to four months of age. Thirdly, if this hypothesis is correct, combining the integrated approach with pharmaceutical intervention should improve outcomes in infants diagnosed with GORD.