Multiple or persistent crying, sleeping, or feeding problems in early childhood (regulatory problems, RPs) predict increased risk for self-regulation difficulties. Sensitive parenting may protect children from trajectories of dysregulation. Considering self-regulation from a life-course perspective, are children with early multiple and/or persistent RPs affected similarly by parenting as those without (main effects model, ME), or are they more vulnerable (diathesis-stress, DIA-S), or more susceptible (differential susceptibility theory, DST) to variations in sensitive parenting at age 6 years? Participants (N = 302) were studied prospectively from birth to 28 years. RPs were assessed from 5 to 56 months. Sensitive parenting was observed at 6 years. Attention regulation was observed at 8 and 28 years. Internalizing and externalizing problems were rated by parents at 8 years, and by adults at 28 years. Confirmatory-comparative modelling tested whether associations of sensitive parenting with outcomes at 8 and 28 years among individuals with early multiple and/or persistent RPs (n = 74) versus those without (n = 228) were best explained by ME, DIA-S, or DST models. Best fitting models differed according to age at assessment. For childhood attention regulation, the statistically parsimonious DIA-S provided the best fit to the data. At age 28, two additive main effects (ME, RP group and sensitive parenting) fit best. DIA-S and ME explained internalizing and externalizing problems. Using a comprehensive life-span approach, DIA-S and ME models but not DST explained how early RPs and sensitive parenting predicted attention, internalizing, and externalizing outcomes. Individuals with early RPs are vulnerable to insensitive parenting.