The study aimed to assess the extent to which teachers' perceptions of their school principal's instructional leadership may explain teachers' perceptions of 21st century pedagogy via the mechanisms of teachers' job satisfaction with professional development processes and their empowerment. A sample of 645 teachers affiliated with 64 Israeli public junior high schools responded to a quantitative questionnaire. Using multilevel structural equation modeling (MSEM), we found a positive relationship between the principal's instructional leadership and teachers' satisfaction with professional development (PD) processes; between teachers' satisfaction with PD processes and teachers' empowerment; and between teachers' empowerment and the three dimensions of 21st century pedagogy. Teachers' satisfaction with PD and teachers' empowerment mediated the relationship between the principal's instructional leadership and 21st century pedagogy. The study contributes to the knowledge on the link between principals' instructional leadership and pedagogy, and, specifically, to 21st century pedagogy. Instructional leaders need to be more engaged in empowering teachers, use expert knowledge about student learning, create and share knowledge among school members, and emphasize pedagogic rather than administrative tasks. As pedagogical leaders, school principals need to allow teachers to influence the design of PD processes and encourage them to participate in PD processes that will prepare them to adopt 21st century pedagogy.