Significance The interplay between microRNAs and the cell-cycle machinery in vivo remains poorly understood. Here we report that the microRNA family miR-34/449 plays an essential and rate-limiting role in repressing cell-cycle proteins and enforcing cell-cycle exit during epithelial cell differentiation. We demonstrate that genetic ablation of the entire miR-34/449 family leads to derepression of cell cycle-promoting proteins in differentiating epithelial cells, thereby preventing their timely cell-cycle exit. This, in turn, impairs epithelial ciliation and leads to profound developmental defects. Hence, this study describes a function of the miR-34/449 family in linking cell proliferation and differentiation.