The direct targeting of the Anaplastic Lymphoma Kinase (ALK) in high-risk neuroblastoma (hrNB), a predominantly pediatric extracranial cancer of neural crest origin, has the potential to significantly improve the overall survival of patients whose disease is driven by mutations in or amplifications of ALK. The preclinical testing of ALK inhibition (ALKi), specifically utilizing the macrocyclic ATP-competitive inhibitor lorlatinib, has provided rationale to move ALKi to upfront therapy in combination with standard-of-care for a subset of hrNB patients. As patients with ALK-driven relapsed/refractory hrNB receive lorlatinib as a part of their salvage therapy, it has become strikingly evident that the robust and potent effect by lorlatinib is not sustained, as resistance to the compound eventually occurs in a proportion of the patients, after which no known curative options exist. Additionally, ALK drives disease in only a subset of patients, and is crucial to also characterize other drivers of hrNB to develop novel therapeutic strategies and improve outcomes for patients, similar to the ALKi experience. Thus, it is absolutely paramount to elucidate drivers of primary and resistant disease. A major preclinical challenge is to model faithfully resistant disease as observed in the clinical setting. Therefore, we aimed to develop models of lorlatinib resistance in vitro and in vivo to closely resemble the clinical manifestation of resistant disease and characterize thoroughly other drivers of primary and relapsed disease. We leveraged novel insights from the characterization and hypothesized that epigenetic reprogramming is a major contributor to resistance, and aimed to elucidate non-mutational drivers of disease to target the epigenome in order to prevent and overcome resistant disease. Through the studies herein, we describe the lorlatinib-resistant models we generated, the characterization of additional therapeutically tractable drivers of disease, and the novel therapeutic strategy discovered to sensitize naïve and resistant ALK-driven models to lorlatinib.