One of the most ancient and highly conserved microRNAs (miRNAs), the let-7 family, has gained notoriety owing to its regulation of stem cell differentiation and essential role in normal development, as well as its tumor suppressor function. Mechanisms controlling let-7 expression have recently been uncovered, specifically the role of the RNA-binding protein Lin28 – a key developmental regulator – in blocking let-7 biogenesis. This review focuses on our current understanding of the Lin28-mediated control of let-7 maturation and highlights the central role of Lin28 in stem cell biology, development, control of glucose metabolism, and dysregulation in human disease. Manipulating the Lin28 pathway for the precise control of let-7 expression may provide novel therapeutic opportunities for cancer and other diseases.