The descriptive literature on people with Down syndrome shows a behavioural phenotype characterized by both strengths and weaknesses. Relative strengths include visual processing and social development, both of which can be capitalized on to design classroom interventions that enhance learning. Demonstrated weaknesses include expressive communication, short-term memory, and some aspects of motor development, along with decreased task persistence and avoidance of difﬁcult tasks. These weaknesses are of critical concern because corresponding impairments are likely to negatively impact learning from a young age. Developing ways to ensure learners are motivated to engage in instruction, acquire pivotal skills, and have opportunities that build upon strengths are key to ensuring optimal outcomes. The science of applied behaviour analysis (Carr et al., 1999; National Autism Center, 2009) provides a starting point to integrate an understanding of behavioural phenotype with evidence-based interventions, an approach that may signiﬁcantly improve learning and long-term outcomes. This integration of ﬁelds had occurred for learners with autism and had been suggested speciﬁcally in relation to challenging behaviour (Robinson Joy, 2009) and for learners with Down syndrome (Fidler, Most, & Philofsky, 2008). In this chapter, we consider behaviours that interfere with classroom performance, pivotal skills, and strengths that may enhance classroom performance, as well as the role of intervention intensity. We review related interventions, suggest applications with learners with Down syndrome, and provide directions for future research.