Gastrointestinal, pancreatic, and hepatic signs and symptoms represent the most common presentation of early disease among patients with cystic fibrosis and may be the initial indication of disease. Regardless of whether cystic fibrosis is diagnosed early by newborn screening or later by clinical course, the impact of gastrointestinal, pancreatic, and hepatic manifestations on early life is nearly ubiquitous. Conditions strongly linked with cystic fibrosis, such as meconium ileus and pancreatic insufficiency, must be recognized and treated early to optimize both short- and long-term care. Similarly, less specific conditions such as reflux, poor weight gain, and cholestasis are frequently encountered in infants with cystic fibrosis. In this population, these conditions may present unique challenges in which early interventions may have significant influence on both short- and long-term morbidity and mortality outcomes.