This study investigated the role of parental Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and depressive symptoms on parenting stress in 174 families with children with ASD and/or ADHD, using generalized linear models and structural equation models. Fathers and mothers reported more stress when parenting with their child with ASD and/or ADHD than when parenting with the unaffected sibling; they also experienced more stress than a norm population. Depressive symptoms were most pronounced in the parents of children with ASD and ASD+ADHD. Spouse correlations were found for ASD, depression, and parenting stress. Paternal ASD and maternal ADHD symptoms were related to increased parenting stress, and parental ADHD symptoms with depressive symptoms and parenting stress. The results highlight the increased burden of raising a child with ASD and/or ADHD and the reciprocal relationship this has with parents’ ASD, ADHD, and depressive symptoms, and levels of stress.