The discovery of microRNA (miRNA) has provided new and powerful tools for studying the mechanism, diagnosis and treatment of human cancers. The down-regulation of tumor suppressive miRNA by hypermethylation of CpG island (CpG is shorthand for 5′-C-phosphate-G-3′, that is, cytosine and guanine separated by only one phosphate) is emerging as a common hallmark of cancer and appears to be involved in drug resistance. This review discusses the role of miRNA and DNA methylation in drug resistance mechanisms and highlights their potential as anti-cancer therapies in Anaplastic Lymphoma Kinase (ALK)-positive lymphomas. These are a sub-type of non-Hodgkin’s lymphomas that predominantly affect children and young adults and are characterized by the expression of the nucleophosmin (NPM)/ALK chimeric oncoprotein. Dysregulation of miRNA expression and regulation has been shown to affect several signaling pathways in ALK carcinogenesis and control tumor growth, both in cell lines and mouse models. These data suggest that the modulation of DNA methylation and/or the expression of these miRNA could serve as new biomarkers and have potential therapeutic applications for ALK-positive malignancies.