Teachers are responsible for identifying and instructing an increasingly diverse population of student readers. Advances in educational technology may facilitate differentiated instruction. Using data from a large, population-based sample of third-grade students, we investigated "what works for whom" in technology-based literacy instruction. We classified 594 students into four reader subgroups or "profiles" based on two scores from a readily-available, commonly-used progress monitoring tool (aimsweb©). Using this simple and accessible method, we identified profiles of readers that resemble the poor decoder, poor comprehender, mixed deficit, and typical reader subgroups found in past studies that used extensive test batteries or advanced statistics. We then employed nonparametric analyses to examine both proximal and distal outcomes across one academic year. First, we compared the relative progress of reader profiles on a technology-based reading program (Lexia® Core5® Reading). Second, we determined whether each reader profile made gains on aimsweb at the end of the year. We found that Core5 effectively differentiated online instruction and contributed to improved aimsweb performance for most reader profiles. The findings from this study help inform educational best practices for efficient identification of and effective intervention for all students.