Medically unexplained symptoms (MUS) are a rising entity particularly among adolescents that might be highly impairing. In the past, many terms such as psychosomatic symptoms, somatisation, functional disorders, somatoform disease have been used to define a heterogeneous group of physical symptoms without any organic underlying disease, but somehow related to emotional or psychological aspects of the patients’ life. Recently, the term MUS has been preferred as it captures the full range of conditions characterized by persistent physical symptoms that cannot yet be explained by any medical illness or injury. In the last years, there has been an increasing interest about MUS, which represent a significant disorder among adolescents, particularly in females. At present, MUS in adolescents is a great challenge for paediatricians and primary care physicians, but since its prevalence is increasing, it will become even more relevant in the next years. Necessarily, adolescents with unexplained physical symptoms and their families seek out medical assistance, through the general paediatrician, disease specialists or the emergency department. However, medical assistance itself, if not adequate or delayed, can maintain or even worsen the symptoms in an escalating vicious circle. The result is often cyclic disability, frustration and missed opportunities to collaborate to enhance the patient functionality. On the other hand, many paediatricians have inadequate knowledge of MUS and its approach, evaluation and management. Thus, my report will focus on MUS and specifically on epidemiological and on its variable clinical presentation. I will also discuss the possible risk factors for MUS especially focusing on adolescent’s personality and emotional disorders, cognitive and learning difficulties, previous adverse life or traumatic events, family medical or psychiatric history and on the school and peer group environment. Furthermore, the optimal evaluation strategy, which requires a comprehensive multidisciplinary approach, including medical and psychosocial assessment, will be extensively discussed. Such integrate way to manage adolescents with MUS should limit the high, often disproportionate, amounts of medical interventions required, such as numerous ER visits or hospitalizations, and unnecessary investigations. Last but not least, I will outline the successful management strategy for MUS. Primarily, engagement of families and patients is crucial; psychotherapy and physiotherapy are also winning weapons, whether associated with a good alliance between patient, family and paediatrician. Frequently, the appropriate intervention should also include an early psychiatric referral. In fact, a strict collaboration between paediatricians and psychiatrists may promote prompt confirmation of the diagnosis, but also timely treatment could improve the adolescent’s quality life, preventing the social and personal negative consequences. By way of example, I will describe few cases with different clinical presenting features recently admitted to our hospital, providing the details of their diagnostic approach, the multidisciplinary management and outcome.