Down syndrome (DS) has an incidence of about 1/700 births, and is therefore the most common cause of cognitive and behavioral impairments in children. Recent studies on mouse models of DS indicate that a number of pharmacotherapies could be beneficial for restoring cognitive abilities in individuals with DS. Attention deficits that are present in DS account in part for learning and memory deficiencies yet have been scarcely studied in corresponding models. Investigations of this relevant group of behaviors is more difficult in mouse models because of the difficulty in homologizing mouse and human behaviors and because standard laboratory environments do not always elicit behaviors of interest. Here we characterize nest building as a goal-directed behavior that is seriously impaired in young Ts65Dn mice, a genetic model of DS. We believe this impairment may reflect in part attention deficits, and we investigate the physiological, genetic, and pharmacological factors influencing its expression. Nesting behavior in young Ts65Dn mice was severely impaired when the animals were placed in a novel environment. But this context-dependent impairment was transient and reversible. The genetic determinants of this deficiency are restricted to a ∼100 gene segment on the murine chromosome 16. Nest building behavior is a highly integrated phenotypic trait that relies in part on limbic circuitry and on the frontal cortex in relation to cognitive and attention processes. We show that both serotonin content and 5HT2a receptors are increased in the frontal cortex of Ts65Dn mice and that pharmacological blockage of 5HT2a receptors in Ts65Dn mice rescues their context dependent nest building impairment. We propose that the nest-building trait could represent a marker of attention related deficits in DS models and could be of value in designing pharmacotherapies for this specific aspect of DS. 5HT2a modulation may improve goal-directed behavior in DS.