Cleft lips, alveolar ridges and palates are among the most common birth defects. There are over 500 different complex genetic disorders that include cleft defects. The most common related defects include abnormalities of the skeleton, skull, cardiovascular and nervous system. The occurrence of a cleft results from the interplay of multiple genes and environmental factors. Several thousand different mutations responsible for these syndromes have been discovered, whereas there are still numerous phenotypic cases of unknown genetic origin. The aim of this study was to present various clinical aspects and the latest discoveries with regard to genetic research in complex malformations, such as Van der Woude syndrome, popliteal pterygium syndrome, EEC syndrome, Pierre Robin sequence, various forms of Stickler syndrome, and Treacher Collins syndrome. These complex syndromes have different incidences, and most of them also have allelic variants with characteristic severities that differ even among close relatives. Easier access to genetic counseling and the lower cost of DNA testing in recent years can lead to new findings on the causes of such syndromes.