Impactions of mandibular second molars due to posterior dental crowding pose difficulties for orthodontic treatment. It is important to know aspects related to genetics and epigenetics of tooth eruption as well as orthodontic, surgical or combined treatment alternatives for these cases. The present review highlights the key role of the MSX1 gene during the intraosseous eruption process as an initiator of one of the three normal eruptive events, as well as that of other local environmental or epigenetic alterations under which this challenge in orthodontic treatment may originate. In addition, the existing surgical, non-surgical, and combined alternatives to solve these treatment difficulties will be indicated.