Floppy infant syndrome is a disease in which infants present with generalized hypotonia at birth or early infancy. There are many possible etiologies, which make a specific diagnosis difficult. The expanding knowledge of genetic disorders has made noninvasive genetic testing available for specific diagnoses. Therefore, it is very important for clinicians to use a systematic approach for the investigation of such children. In this chapter, I review the many possible etiologies of the floppy infant syndrome, and a systematic approach for the evaluation of this disorder will be proposed.