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Research involving students with LD, ADHD, and/or ASD is fraught with challenges. These include difficulty in recruitment to achieve sufficient statistical power, bias and loss of N as a result of high attrition rates which are not independent of the underlying disabilities, high variability and comorbidity within the population, and low accessibility and validity of many instruments for this population. This paper will report on two NSF funded research projects (HRD-1128948 and HRD-1420198) implemented at a college that exclusively serves students with LD, ADHD, and/or ASD. One study employed a between-subjects quasi-experimental design while the other employed a within-subjects repeated measures design. The strengths and challenges of these designs for this population are compared and contrasted.