Ventricular septal defects (VSDs) are the most common type of heart malformation and may occur like a part of a syndrome or as an isolated form. Clinical manifestations are related to the interventricular flow, which is determined by the size of the defect. Aiming at the identification of genetic causes is important in both syndromic and non-syndromic forms of VSD, to estimate the prognosis and choose the optimal management. Other reasons of the identification of genetic factors in the etiopathogenesis include the assessment of the neurodevelopmental delay risk, recurrence in the offspring, and association with extracardiac malformations. The diagnostic process has been improved, and currently, the use of the most suitable and accessible technique in the clinical practice represents a challenge. Additional advantages in genetic testing were brought by next-generation sequencing technique, various testing panels being available in many laboratories.