Children with cancer experience repeated invasive and painful medical procedures. Pain and distress does not decrease with repeated procedures and may worsen if pain is not adequately managed. In 1990, the first recommendations on the management of pain and anxiety associated with procedures for children with cancer were published. Guiding principles described in the recommendations continue to hold true today: maximize comfort and minimize pain, use nonpharmacologic and pharmacologic interventions, prepare the child and family, consider the developmental age of the child, support family and child involvement, assure provider competency in performing procedures and sedation, and use appropriate monitoring to assure safety. This article reviews these key components for managing painful procedures in children and reviews the latest pharmacological and nonpharmacological interventions most effective in minimizing pain and discomfort.