Parenting children with neurodevelopmental disabilities is often challenging. Biological mothers of children with Fragile X Syndrome (FXS) may be susceptible to increased risk of mental health problems. This study examined the longitudinal relationships between maternal mental health, child challenging behaviors, and mother-child relationship quality in children and adolescents with FXS. Fifty-five mother-child dyads were followed from childhood into adolescence. The findings suggest that child challenging behaviors, maternal mental health, and mother-child relationship quality were stable during that period. Additionally, elevated levels of child challenging behaviors negatively impacted maternal mental health. Finally, child challenging behaviors, in combination with maternal mental health, influenced mother-child relationship quality. Clinical implications are discussed.