Respiratory insufficiency can be a presenting symptom of Congenital Myasthenic Syndromes (CMS) but is rarely recognized as such. CMS result from failure of the neuromuscular transmission secondary to gene mutations affecting the neuromuscular junction structure and function. A core symptom is muscle weakness that worsens with physical exertion. We describe five children who experienced severe to life threatening episodes of respiratory insufficiency, especially during viral infections, due to respiratory muscle weakness. During infections they often also had progression of their ocular, facial, and limb muscle weakness. All children were eventually diagnosed with genetically proven CMS. In all five children, treatment with pyridostigmine, an acetylcholinesterase inhibitor, resulted in clinical improvement. CMS should be considered in every patient with unexplained recurrent respiratory insufficiency, or with a disproportionate and unusually severe course of a (viral) respiratory infection. Early diagnosis of CMS is crucial for early treatment, which may help avoiding further deterioration of the muscle strength, severe respiratory insufficiency and sudden infant death.