Research has shown elevated mood, anxiety, and stress in mothers of children with developmental disabilities. These findings remain ambiguous due to inconsistencies in the definitions and groupings of maternal disorders, measurement instruments used, and inadequate samples. The behavioral overlap between these disorders permits examination of the association between the autistic and/or problem behavior of children and maternal mood, anxiety, and stress. This study examines the frequency and predictors of mood, anxiety, and stress in mothers of three groups: children with FXS, children with FXS/autism, and children with autism. Lifetime and current mood and anxiety disorders and current levels of stress were assessed in 56 mothers of children with the full mutation of FXS, 19 mothers of children with the full mutation of FXS and autism, and 38 mothers of children with autism. Mothers of children with autism reported increased rates of generalized anxiety disorder (GAD) compared to mothers of children with FXS or FXS/autism. A greater proportion of mothers of children with autism reported experiencing two or more mood or anxiety disorders over their lifetime than mothers of children with FXS. Child problem behavior predicted maternal mood, anxiety, and stress across all groups. Autistic symptomatology of the child predicted maternal stress. In the majority of mothers, the initial onset of a reported mood or anxiety disorder was prior to the birth of the child, suggesting that childrearing burden cannot fully explain mood and/or anxiety in these mothers. The environmental and/or genetic contributions related to increased rates of GAD in mothers of children with autism compared to mothers of children with FXS should be examined further. Future studies should compare frequency of mood and anxiety in mothers of these groups to population estimates. Intervention and support services for mothers of children with FXS and autism should focus on reducing maternal stress by assisting them to manage the autistic and/or problem behavior of the child.