The endogenous mediators of RNAi, microRNA (miRNAs), have grown in our understanding to be nodal elements in molecular homeostasis. Deregulation of miRNA levels is now believed to frequently cause disease. Considerable excitement therefore surrounds efforts focusing on restoring aberrant miRNA expression as a novel approach to therapy. In Chapter 7, the current body of knowledge around miRNA function in man and clinically relevant laboratory species is critically assessed from a miRNA biotherapeutics safety and efficacy perspective. In addition, the major relevant lessons learnt from RNAi and antisense drug development efforts are discussed where these translate to the field of miRNA therapy. Special attention is paid to key elements, such as evolutionarily optimized, viral vectoring solutions and genomic organization contexts that can be exploited for tailoring ectopic miRNA expression, maturation and bioprocessing. Moreover, the knowledge gaps arising from common approaches used to interrogate miRNA mode of action are identified in support of developing robust clinical path strategies in the personalized, precision medicine era.