Pediatric nonadherence to medication is a significant public health problem, and rigorous research repeatedly documents that nonadherence increases risk for hospitalization, healthcare cost, disease progression, and death. Participants in our previous studies have described medication adherence as “one of the most stressful parts” of pediatric cancer caregiving, and we found that 93% of parents experience barrier(s) to medication administration. We have designed MedSupport, a theory-based multilevel intervention that is designed to address root barriers to medication adherence. In Aim 1 we will determine if the MedSupport intervention increases the proportion of patients with chemotherapy adherence 95% or higher. Our study design leverages a unique opportunity as a companion study for an upcoming therapeutic trial and will enroll at 8 pediatric cancer programs. This will enhance methodological rigor through leveraging robust clinical trial infrastructure to achieve multi-site recruitment in diverse geographic and clinical sites. We will recruit families of pediatric patients with ALL (N = 150) on home-based chemotherapy. Families will be randomized 1:1 to (1) the MedSupport intervention and (2) usual care with standardized education control. We will use both MEMS electronic medication monitoring and innovative biomarkers of drug metabolites to measure adherence. In Aim 2 we will test a theory-based mechanism of intervention effectiveness. These results will increase conceptual significance through rigorous examination of mechanisms of action of the MedSupport intervention to inform future intervention optimization and translation. In Aim 3 we will use the Implementation Outcomes Framework to examine implementation effectiveness to enhance future dissemination of the MedSupport intervention. We will examine the relationship between implementation quality on intervention effectiveness (Aim 3a) and strategies that may hinder or support uptake within routine care to inf