The use of oral sucrose has been the most extensively studied pain intervention in newborn care to date. More than 150 published studies relating to sweet-taste-induced calming and analgesia in human infants have been identified, of which 100 (65%) include sucrose. With only a few exceptions, sucrose, glucose, or other sweet solutions reduced pain responses during commonly performed painful procedures in diverse populations of infants up to 12 months of age. Sucrose has been widely recommended for routine use during painful procedures in newborn and young infants, yet these recommendations have not been translated into consistent use in clinical practice. One reason may be related to important knowledge and research gaps concerning analgesic effects of sucrose. Notably, the mechanism of sweet-taste-induced analgesia is still not precisely understood, which has implications for using research evidence in practice. The aim of this article is to review what is known about the mechanisms of sucrose-induced analgesia; highlight existing evidence, knowledge gaps, and current controversies; and provide directions for future research and practice.