Among symptoms that patients with neurodevelopmental disorders can exhibit, challenging behaviors (CBs) are some of the more complex to face, both for caregivers and the patients themselves. They are more frequent in individuals with severe autism spectrum disorders and intellectual disability, and during the transition period from late childhood to young adulthood. Here, we offer an overview of the therapeutic approaches proven worthy in managing CB. Topics include nonpharmacologic treatments (such as behavioral and family interventions), drug prescriptions, and specific intensive care for life-threatening situations, including inpatient stay in specialized neurobehavioral units. Then, we focus on rare, complex, and resistant clinical presentations, mainly based on the authors' clinical experience. We propose a multimodal intervention framework for these complex presentations, embracing developmental and dimensional approaches. A case presentation illustrates the proposed framework, with the aim of serving readers and health practitioners that are facing such cases.