Cystic fibrosis (CF) is a relatively common disease seen in Whites of northern European descent. Classically, it was a lethal disease and uncommon for the orthopedic practitioner to interact with CF patients. Recent pharmaceutical breakthroughs targeting the CF transmembrane conductance regulator (CFTR) gene have significantly prolonged patient life expectancy. This makes it increasingly likely that orthopedic surgeons will encounter CF patients in their clinic. In this article, the authors discuss pertinent musculoskeletal manifestations of the CF population, including the increased risk of decreased bone mineral density and bone mineral content, muscle deconditioning, spinal kyphosis, fractures, and elevated systemic inflammation predisposing these individuals to CF-related arthralgia. The diagnoses are grouped into subspecialties (arthroplasty, pediatrics, spine, sports, and trauma) most likely to evaluate the patient. Additionally, the authors review treatment options for these conditions and discuss the need for these patients to be seen in the perioperative period by their CF care team for patient optimization due to their diminished pulmonary function. Interspersed with this literature review, the authors present 2 unique cases. The first case details a patient with pain over her spine due to multilevel spinous process bursitis caused by a high-frequency chest wall oscillation system, which masquerades as an infection. The second case is a non-contact midsubstance rectus femoris tear in an athlete. These cases highlight the need for increased vigilance for uncommon diagnoses in the CF patient population. [Orthopedics. 2021;44(3):e440-e445.].