Cellular transitions occur at all stages of organismal life from conception to adult regeneration. Changing cellular state involves three main features: activating gene expression necessary to install the new cellular state, modifying the chromatin status to stabilize the new gene expression program, and removing existing gene products to clear out the previous cellular program. The maternal-to-zygotic transition (MZT) is one of the most profound changes in the life of an organism. It involves gene expression remodeling at all levels, including the active clearance of the maternal oocyte program to adopt the embryonic totipotency. In this chapter, we provide an overview of molecular mechanisms driving maternal mRNA clearance during the MZT, describe the developmental consequences of losing components of this gene regulation, and illustrate how remodeling of gene expression during the MZT is common to other cellular transitions with parallels to cellular reprogramming.