The aim of this longitudinal study was to examine the association of infant fussing and crying with self-regulation in toddlerhood and the preschool years, as well as the moderating role of maternal sensitivity therein. When children (n = 149, 53.69% boys) were 6 months old, parents reported on their fussing and crying using a cry diary, and maternal sensitivity was coded during a novel toy procedure. Children participated in various tasks to assess self-regulation in toddlerhood (18 months) and the preschool years (4.5 years). Results indicated that the relation between infant fussing and preschool self-regulation took the shape of an inverted U, but only for children of highly sensitive mothers. For infants of less sensitive mothers, fussing was not related to later self-regulation. Crying was unrelated to preschool self-regulation. Neither fussing, crying, nor maternal sensitivity predicted self-regulation in toddlerhood. The findings support the optimal arousal theory, by demonstrating that for infants of highly sensitive mothers, moderate amounts of low intensity negative reactivity are associated with enhanced self-regulation in the preschool years.