MicroRNAs (miRNAs) are remarkably effective regulators of gene expression at the posttranscriptional level with the ability to control a plethora of biological pathways and cellular functions through interactions with a wide range of target genes. This makes miRNAs highly attractive as therapeutic tools to restore altered cell functions associated with disease phenotypes. Nevertheless, this advantage of miRNAs also presents a significant drawback: their extensive cellular effects make it challenging to avoid off-target effects. Here, this chapter highlights the advances made on miRNAs toward therapeutic applications, the primary challenges and strategies for overcoming obstacles, and those that successfully entered clinical trials.