Globally, classrooms at all levels of education are progressively becoming more and more culturally and racially diverse, necessitating the need for instructors who are competent in Culturally Responsive Instruction (CRI). Previous empirical studies have unequivocally demonstrated that teachers' beliefs have a significant impact on the instructional choices and methods they use. Although CRI has been advocated as a way to address the cultural diversity and difficulties that can arise in the classroom, little is known about teachers' attitudes toward CRI and the difficulties that can arise in the classroom, particularly in Tanzania, a developing country with more than 120 ethnic tribes. Therefore, the present study, which is based on Vygotsky's sociocultural theory, was pioneered to investigate pre-primary school teachers' perceptions of culturally responsive instruction (CRI) in rural Tanzania and the difficulties they encounter in making their classrooms culturally responsive. This study draws on data from in-depth semi-structured interviews with six (N = 6) pre-primary school teachers from three districts of rural Tanzania. Results indicate that teachers believe that CRI enhanced students' learning in the classroom. The results further showed that teachers firmly believed that CRI enhances teachers' classroom instructional practices. The main difficulties for pre-primary schoolteachers to be culturally responsive in their classes were cited as being their lack of acquaintance with the pupils' cultures and the sheer number of students. Along with recommendations, implications for teacher education, practice, and policy are discussed.