Children with serious illnesses may have special needs that are not strictly clinical in nature and that are not always easily discerned. The capacity to detect and respond to this type of need becomes an increasingly important focus in palliative care. Spiritual care falls within this sphere of interest, for both the child with an illness and their family. In the care of children with advanced cancer and other life-threatening illnesses, spiritual care providers partner with families as they navigate a life-threatening illness, offering empathy, spiritual companionship, and guidance in balancing personal beliefs, values, and medical decision-making. This chapter will explore the history and study of spiritual care of children with life-threatening illnesses and their families and present practical approaches for spiritual screening and intervention, as well as mechanisms for enhancing the infrastructure within healthcare settings to promote exemplary spiritual care.