In this article, I illustrate how research from cognitive science and the science of reading can inform research on the science of reading instruction. This purpose is accomplished by focusing on four recently published randomized control trials of instruction designed to teach alphabet letters to 3- and 4-year-old children (N = 342) attending preschool in the United States. Approximately 35% of the children were dual-language learners. Instruction ranged from 10 to 12 weeks' duration and was implemented in small groups taught by research assistants. Evidence for the value of explicit instruction in which paired-associate learning connecting visual letter forms with their verbal letter labels (names and sounds) for learning letters is reviewed. The effectiveness of explicit instruction for promoting children's motivation and engagement is identified. The relation of these studies to important features of a science of reading is discussed. Collective and individual instructionally related implications from the studies are elaborated, including replicated evidence of the benefit of visual-verbal paired-associate learning of printed letters and their spoken names or sounds; the positive effects on motivation and engagement of such instruction; and the benefit of decontextualized letter instruction over letter instruction contextualized within storybook reading, real words, and personal names.