Although numerous studies have identified a correlational relationship between vocabulary and comprehension, we know less about vocabulary interventions that impact reading comprehension. Therefore, this study is a systematic review of vocabulary interventions with comprehension outcomes. Analyses of 36 studies that met criteria are organized around (a) type of comprehension measure (i.e., comprehension of passages that included taught words or more generalized comprehension measures) and (b) type of intervention (i.e., direct teaching of word meanings or word-learning strategies). The authors looked for patterns in characteristics of vocabulary instruction within these analyses. Their findings led to four major themes: (1) Teaching of word meanings supported comprehension of text containing the target words in almost all cases; (2) instruction that focused on some active processing was typically more impactful than a definition or a dictionary method for supporting comprehension of text containing the target words, but we do not know how much instruction is sufficient; (3) there is very limited evidence that direct teaching of word meanings, even long-term, multifaceted interventions of large numbers of words, can improve generalized comprehension; and (4) there is currently no empirical evidence that instruction in one or two strategies for solving word meanings will impact generalized comprehension. However, studies that actively teach students to monitor their understanding of vocabulary and to use multiple, flexible strategies for solving word meanings are a promising area for future research. The authors discuss the implications of these themes, as well as critical avenues for future vocabulary research.