The congenital myasthenic syndromes (CMS) are inherited disorders in which the safety margin of neuromuscular transmission is impaired by one or more specific mechanisms. The CMS have been recognized as distinct clinical entities since the 1970s, after the autoimmune origin of myasthenia gravis and of the Lambert-Eaton myasthenic syndromes had been established. Initially, the CMS were delineated by combined clinical, in vitro electrophysiologic, and structural studies. The study of the CMS gained further impetus when sequences of genes coding for EP-associated proteins were determined and with the advent of Sanger sequencing. In the past three years, whole exome sequencing facilitated discovery of novel CMS at an accelerated pace and by now no fewer than 20 CMS disease gene have been identified. Figure 1 shows the distribution of identified CMS disease proteins at the EP. In this review we consider the factors that affect the safety margin of neuromuscular transmission, classify the CMS identified to date, describe their distinguishing features and pathogenesis, and consider available therapies.