MicroRNAs (MiRNAs) are a class of endogenously encoded ~ 22 nucleotide, noncoding, single-stranded RNAs that contribute to development, body planning, stem cell differentiation, and tissue identity through posttranscriptional regulation and degradation of transcripts. Given their importance, it is predictable that dysregulation of MiRNAs, which target a wide variety of transcripts, can result in malignant transformation. In this review, we explore the discovery of MiRNAs, their mechanism of action, and the tools that aid in their discovery and study. Strikingly, many of the studies that have expanded our understanding of the contributions of MiRNAs to normal physiology and in the development of diseases have come from studies in the hematopoietic system and hematologic malignancies, with some of the earliest identified functions for mammalian MiRNAs coming from observations made in leukemias. So, with a special focus on the hematologic system, we will discuss how MiRNAs contribute to differentiation of stem cells and how dysregulation of MiRNAs contributes to the development of malignancy, by providing examples of specific MiRNAs that function as oncogenes or tumor suppressors, as well as of defects in MiRNA processing. Finally, we will discuss the promise of MiRNA-based therapeutics and challenges for the future study of disease-causing MiRNAs.