A recurrent theme in much of the contemporary HIV behavioral and social science research is that ecological approaches that acknowledge the interplay of structural, institutional, and individual-level factors are essential to improve HIV prevention efforts in racial/ethnic minority communities. Similarly, an ecological approach provides an innovative framework for understanding the challenges that many racial/ethnic minority HIV prevention researchers face in their quest to transition from mentored researcher to independent researchers. Informed by an ecological framework, and building on our experiences as two racial/ethnic minority women HIV prevention researchers who transitioned from a formal research mentorship relationship to become independent HIV prevention researchers — principal investigators of NIH-funded R01 grants —, we frame our discussion of the mentored to independence research trajectory with a focus on structural, institutional, and individual determinants. Throughout, we integrate suggestions for how institutions, mentors, and HIV prevention researchers can facilitate the final frontier from mentored research to independence.