Data indicate that females and ethnic/race minority groups are underrepresented in the science and engineering workforce calling for innovative strategies to engage and retain them in science education and careers. This study reports on the development, delivery, and outcomes of a culturally driven science, technology, engineering, mathematics (STEM) program, "iSTEM," aimed at increasing engagement in STEM learning among Native American 3rd-8th grade students. A culturally relevant theoretical framework, Funds of Knowledge, informs the "iSTEM" program, a program based on the contention that the synergistic effect of a hybrid program combining two strategic approaches (1) in-school mentoring and (2) out-of-school informal science education experiences would foster engagement and interest in STEM learning. Students are paired with one of three types of mentors: Native American community members, university students, and STEM professionals. The "iSTEM" program is theme based with all program activities specifically relevant to Native people living in southern Arizona. Student mentees and mentors complete interactive flash STEM activities at lunch hour and attend approximately six field trips per year. Data from the "iSTEM" program indicate that the program has been successful in engaging Native American students in "iSTEM" as well as increasing their interest in STEM and their science beliefs.