Annually, at least 21 million children could benefit from pediatric palliative care (PPC) and 8 million would need specialized PPC services. In the USA alone, more than 40,000 children aged 0–19 years die annually; 55% of them are infants younger than 1 year of age. Pain is common, under-recognized, and under-treated, especially in children with progressive neurodegenerative and chromosomal conditions with central nervous system impairment. Unrelieved pain is also common in children with advanced serious illness during the end-of-life period, and, when treated, the therapy is commonly ineffective. Treating pain in children with serious illness is not profoundly different than advanced pain management for children with complex acute conditions or diseases such as major trauma, burns, cancer, or those with sickle cell disease in vaso-occlusive crisis. It is important to appreciate that children with serious illness are more likely to simultaneously suffer from acute pain, neuropathic pain, visceral pain, total pain, and chronic pain. As such, multimodal analgesic (i.e., multiple agents, interventions, rehabilitation, psychological modalities, and integrative (“nonpharmacologic,” e.g., behavioral, physiological, and psychological) therapies that act synergistically for more effective pediatric pain and symptom control with fewer side effects than a single analgesic or modality must be employed. Opioids, such as morphine, fentanyl, hydromorphone, oxycodone, and methadone, remain the mainstay medications to effectively treat pain in children with serious illness. However, medications alone are often insufficient for optimal pain control. In fact, the paradigm shift away from “medications only” toward offering “multimodal analgesia” to children with serious illness experiencing pain, including addressing chronic pain/primary pain disorders and total pain has become a “game changer” in advancing PPC to ensure that patients can live as long as possible, as well as possible.