This case study describes the challenges we faced when using culturally responsive research methodologies in an international mental health research context. Our work focused on evaluating the use of Western-based mental health care treatments in Cambodia. Utilizing culturally responsive methodologies allowed us to meticulously evaluate the impact of system, context, culture, power, needs, and beliefs of each unique individual participant and family and conduct the research around participants’ mental health needs. Responsive methodologies diverge from traditional methodologies by intentionally addressing participant cultural values that affect recruitment, participation, retention, and distrust in the research process. They allow conceptualization of research goals, design, and process with stakeholders’ values in mind, even when these components do not merge with the dominant culture’s research aims. Drawing on observational field notes and journaling data from two responsive evaluation studies in Cambodia, we discuss challenges of using culturally responsive research methodologies and explore issues surrounding preparation for the project, obtaining funding and consent, creating and maintaining relationships and support, and addressing ethical issues. We provide suggestions for working internationally and ways researchers can be more flexible.