The maternal-to-zygotic transition (MZT) is a universal step in animal development characterized by two major events: activation of zygotic transcription and degradation of maternally provided mRNAs. How zygotic gene products instruct the degradation of maternal messages remains a long-standing question in biology. MicroRNAs (miRNAs) have recently emerged as widespread regulators of gene expression. miRNAs control temporal and spatial gene expression by both accelerating the decay of mRNAs from previous developmental stages and modulating the levels of actively transcribed genes. In this review, I discuss recent studies of the roles of miRNAs during the maternal-to-zygotic transition and cellular reprogramming, where they reshape transcriptional landscapes to facilitate the establishment of novel cellular states.