Persons experiencing severe and persistent mental illness (SPMI) constitute a small but vulnerable population in healthcare and society. Nonetheless, it is advocated to involve people with SPMI in research to improve how care is provided to them. However, qualitative research with this population is challenging due to several factors, including (self-) stigma, assessment of decision-making capacity, reduced communication skills, and the (perceived) risk of adverse events, resulting in relative scarcity in academic interest and scientific publications. In this contribution, the authors share their practical experiences in conducting qualitative research among this group of people, specifically focusing on sensitive topics including end-of-life care and palliative care approaches. Both beneficial and challenging factors encountered across the different research stages are systematically delineated and reflected upon. Qualitative research involving persons with SPMI necessitates a different perspective on methodology and requires specific competencies from researchers. As might be expected, adequate preparation, thorough follow-up, and support for all involved are critical success factors. Additionally, however, it may also require adopting a somewhat unconventional approach to qualitative interviewing, encouraging creativity and ethical reflection as guiding principles. Exploring alternative methodologies and non-conventional engagement in research could provide a much-needed voice to individuals who are currently unrepresented in the research discourse.