Nearly half of all youths experience a mental health disorder at some point during childhood (Merikangas et al., 2010). Pediatric psychopathology is associated with a substantial amount of impairment in the school, social, and home domains, and such symptoms can have adverse impacts on subsequent development (Beauchaine & Hinshaw, 2013; Patel, Flisher, Hetrick, & McGorry, 2007). Fortunately, a number of medications have demonstrated efficacy in treating a number of mental health conditions (Martin, Scahill, & Kratochvil, 2010). Despite these demonstrated effects, treatment response is often incomplete, and the mechanisms by which pharmacotherapy lead to behavior change are not well understood. However, research in pediatric psychopharmacology has often not considered the role of psychosocial variables, despite their promise to explain much variance in psychiatric outcomes and the robust influence they have demonstrated in psychotherapy-based behavior change (e.g., Shirk & Karver, 2011). This study investigated the role of four psychosocial variables in treatment outcome in pediatric psychiatric practice: medication adherence, therapeutic alliance, motivation for behavior change, and expectancies for positive treatment outcome. Surprising patterns of effects were found, with psychosocial variables being associated with both decreases and increases in symptomology depending on the circumstance (e.g., externalizing behavior), and many inconsistencies were observed among these patterns. While psychosocial variables are often portrayed as having uniformly positive impacts on treatment, their role in pediatric psychiatry may not be as straightforward as is commonly depicted in other diseases and therapeutic approaches. In particular, the nature of their effects on outcome may vary across symptom presentations and intervention approaches. Based on these findings, recommendations for clinical practice and future research are discussed which affect all patients, researchers, and medical providers who participate in pediatric psychiatric treatment.