Engineered DNA-binding proteins have put unprecedented power into the hands of molecular biologists. In a blistering five-year span, the field has seen a revolution in technologies, from the hard-to-construct Zinc Fingers, through the extremely effective TAL Effector (TALE) proteins, to the incredibly simple Cas9 platform. These three proteins, co-opted from nature, are entirely distinct in their origins: ZFs are eukaryotic transcription factors, TALEs are invasive bacterial proteins, and Cas9 is part of a prokaryotic immune system. Still, as different as their sources and even their modes of binding, they share a modularity and programmability that has made them ideal for genome engineering. In understanding and then utilizing these tools for biotechnological purposes, investigators have followed a paradigm: understand the binding, build targeted tools upon the framework, and finally, deploy the tools for therapy. If one looks at papers in the genome engineering field, it's not uncommon to see the same study mirrored for these three platforms. Here, we trailblaze our own course along this well-worn pathway. We first biochemically investigate the binding of TAL Effectors, quantifying the relative affinities of their modular repeats and revealing an unexpected polarity of binding. Next, we take a catalytically inactive Cas9 nuclease and we convert it to a targeted gene-regulation tool that is active at endogenous loci in human cells. And finally, we take up the challenge of delivery and demonstrate successful protein-mediated transduction of both TALEs and Cas9.