Significance We present flySAM, a potent system for Cas9-based transcriptional activation (CRISPRa) in Drosophila . flySAM greatly improves on existing in vivo CRISPRa techniques in terms of potency, scalability, and ease of use, and provides a simple and general method for conducting overexpression experiments and screens. flySAM will now serve as the basis for our growing collection of publicly available CRISPRa transgenic fly lines.