There is reliable evidence that new vocabulary is primarily acquired through wide independent reading. However, struggling readers tend to avoid reading, resulting in limited word encounters and inadequate vocabulary growth, and they often have difficulties inferring the meanings of new words from context. While there are no clear solutions to the problem of vocabulary acquisition for older students with reading difficulties, there are instructional approaches that have some evidence of effectiveness for this population. We describe the research base and promising practices related to three aspects of vocabulary instruction: (1) creating a verbal learning environment that fosters word consciousness, (2) selecting and teaching specific words, and (3) teaching an independent word learning strategy through a combination of contextual and morphemic analysis. These instructional approaches are grounded in overarching principles recognized by researchers as being characteristic of effective instruction for students with learning difficulties, including explicit instruction, promoting cognitive and collaborative engagement, and providing many opportunities for practice, including distributed practice, with teacher feedback. Finally, we discuss the possibilities inherent in a cross-content schoolwide approach to vocabulary instruction at the secondary level. We conclude with a call for additional research examining the effectiveness of instructional approaches to vocabulary development for secondary school students with reading difficulties, including a schoolwide collaborative model.