It has long been established that cancers can become addicted to particular oncogenes. Despite the genetic complexity that governs tumorigenesis, certain cancers can exhibit a critical dependency on the expression of a single oncogene, which when removed leads to death of the cancer cell. Recent observations on the relationships between regulatory RNAs and cancer have revealed that this concept of oncogene addiction extends to microRNAs (miRNAs) as well. Certain cancers exhibit a dependency on the expression of a single oncogenic miRNA, or oncomiR. The field of miRNA biology and its involvement in diseases such as cancer have seen tremendous advances over the past decade. However, little is known about the phenomenon of oncomiR addiction. In this review, we introduce the concept of proto-oncomiRs, or miRNAs that gain oncogenic activity after an initiating event. Furthermore, by highlighting the role of proto-oncomiRs in generating malignant phenotypes, we glean possible insights into the mechanisms that guide oncomiR addiction. In addition, toward the realization of genetically driven personalized medicine, some of the most clinically successful anticancer strategies have involved targeting addictive oncogenes such as HER2, BCR/ABL, EGFR, and VEGF. Elucidating how addictive miRNAs can perpetuate cancer may reveal additional critical molecular targets to exploit for therapeutic purposes. Therefore, in this review, we also summarize the field of anti-miRNA therapeutics, in which antisense and nanoscale delivery technologies are the driving force. Addictive oncomiRs are a double-edged sword; addicted cancers are dependent on oncomiRs that are highly potent therapeutic targets. Dissection of this phenomenon may reveal the mechanisms through which lynchpin miRNAs can perpetuate cancer and present a new paradigm for miRNA-based cancer therapy.