Sickle cell disease (SCD) is one of the most common inherited diseases worldwide. The disease is characterized by chronic hemolytic anemia, as well as acute and chronic complications. One of the most intractable problems encountered by children with SCD is the painful episode that results from tissue ischemia due to vaso-occlusion. Pain related to SCD is unique among pain syndromes due to the unpredictable, recurrent, and often persistent nature of the disease, as well as the recurring and essential need for the use of opioids. Painful vaso-occlusive episodes (VOE) are a principal cause of morbidity and account for a significant number of emergency department and hospital admissions. When untreated or inadequately managed, the pain of VOE may cause both short- and long-term consequences. Despite the fact that pain is an almost universal feature of the disease, children with SCD may form one of the most undertreated and understudied populations. One of the factors contributing to poor pain management is conflicting perceptions between patients, their families, and healthcare professionals about pain that is reported and analgesia that is required. Pain management guidelines have recently been published in an effort to overcome barriers in the assessment and management of pain related to SCD. Although there is considerable variability in the way SCD pain is managed, the standard treatment protocol for painful episodes has been rest, rehydration, and analgesia. However, pain control for children with SCD is often a difficult and complex process, and one that requires frequent systematic pain assessments and continuous adjustment of comfort measures, especially analgesics. There are a variety of analgesic agents to choose from, such as acetaminophen (paracetamol), oral or parenteral nonsteroidal anti-inflammatory drugs, and oral or parenteral opioids. Each of these options has advantages and disadvantages to their use. Continuous infusions of analgesics and patient controlled analgesia have been shown to be effective and widely used in hospital settings to manage severe pain. However, the opioid dose required to achieve pain relief varies considerably within each painful episode, from one episode to another, and between individual patients. Although not yet curable in humans, pain related to SCD can be effectively managed in most patients by using a comprehensive approach that incorporates pharmacologic, psychologic, behavioral, and physical pain management strategies.