Prior research supports the need for elementary-aged students with reading difficulties (RDs) to receive explicit systematic small-group evidence-based reading instruction. Yet for many students, simply receiving evidence-based reading instruction in a small-group setting is insufficient to reach the progress milestones needed to meet grade-level reading standards. The current study examined whether (a) elementary school students with RD constitute homogeneous or heterogeneous groups when considering their basic language and cognitive skills (using a latent profile analysis) and (b) latent profiles are predictive of response to reading comprehension instruction (using a mixed modeling approach). The sample consisted of 335 students, including students with RD and typical students (n = 57). The results revealed heterogeneity within students with RD--there were two distinct profiles, with one having higher basic language (reading fluency and decoding) and cognitive (verbal domain productivity, cognitive flexibility, and working memory) skills and lower attention skills and the other having stronger attention skills and lower basic language and cognitive skills. The findings also suggested that latent profiles were predictive of response to reading comprehension instruction. Our results provide a convincing argument for leading the field in the direction of developing customized interventions. It is conceivable, but remains to be further examined, that researchers and educators could potentially improve reading outcomes through providing a customized reading intervention to a student based on their cognitive-language profile.