Small RNAs are short (approximately 18 to 30 nucleotides), non-coding RNA molecules that can regulate gene expression in both the cytoplasm and the nucleus via post-transcriptional gene silencing (PTGS), chromatin-dependent gene silencing (CDGS) or RNA activation (RNAa). Three classes of small RNAs have been defined: microRNAs (miRNAs), siRNAs and Piwi-interacting RNAs (piRNAs). Research has indicated that small RNAs play important roles in cellular processes such as cell differentiation, growth/proliferation, migration, apoptosis/death, metabolism and defense. Accordingly, small RNAs are critical regulators of normal development and physiology. More interestingly, increasing evidence indicates that small RNAs are involved in the pathogenesis of diverse diseases including cancer, cardiovascular disease, stroke, neurodegenerative disease, diabetes, liver disease, kidney disease and infectious disease. More than 20 clinical trials are ongoing to evaluate therapies based on small RNA. Additionally, small RNAs may serve as novel biomarkers and therapeutic targets for the majority of diseases.