Tooth agenesis is the most common developmental dental anomaly and it is frequently associated with other dento-skeletal disturbances, such as structural variations of other teeth, late dental eruption, transpositions and crowding. Except for the third molars, the mandibular second premolars are the most commonly missing teeth. Oral rehabilitation of patients with missing mandibular premolars often requires a multi-disciplinary approach, and usually results in prolonged treatment time and a greater burden of care. An understanding of the aetiology and clinical features of hypodlontia is essential for the planning phase and the outcome of treatment. The purpose of the present review is, therefore, to discuss the aetiology of hypodlontia as well as to evaluate the clinical options available for the treatment of missing mandibular second premolars. An insight into future research directions and their clinical applications will also be discussed.