The goal of the current study was to examine the complex links among anxious solitude, classroom climate, engagement, achievement, and gender. In particular, drawing upon the differential susceptibility hypothesis (Belsky, 1997), we investigated if children high in anxious solitude were particularly sensitive and responsive to the classroom environment. Participants were N = 712 children in Grade 3, drawn from the National Institute of Child and Human Development (NICHD) Study of Early Child Care and Youth Development data set. Classroom climate and engagement were assessed using the Classroom Observation Scale (NICHD, 1998). Teachers completed the "Teacher Report Form" (Achenbach, 1991) as a measure of anxious solitude and the "Academic Rating Scale" (NICHD, 2010) as a measure of achievement. Hypothesized associations among variables were tested by way of a moderated-mediation model. Among the results, engagement was found to "mediate" the relation between classroom climate and achievement. In addition, anxious solitude and gender were found to "moderate" the relation between classroom climate and engagement. Support for the differential susceptibility hypothesis was found, suggesting that children high in anxious solitude may be more reactive (both positively and negatively) to elements of the classroom environment. In addition, gender differences were observed, indicating that boys may be more responsive to the classroom environment as compared with girls. Implications for future research and educational policies are discussed. Impact and Implications: This study suggests that a classroom environment can foster engagement and achievement among students, however the classroom environment may be particularly influential for students who display anxious behaviors and for boys. Positive classrooms may be especially beneficial for vulnerable students, whereas negative environments may be especially detrimental for vulnerable students. [This study was conducted by the National Institute of Child Health and Human Development (NICHD) Early Child Care Research Network supported by NICHD through a cooperative agreement that calls for scientific collaboration between the grantees and the NICHD staff.]