Growing awareness of the Western perspectives underpinning occupational science and occupational therapy’s values, theories, and evaluation tools has given rise to questions about culturally relevant knowledge and practice with non-Western populations. To make sense of attempts to develop cross-cultural knowledge taking place within the profession and discipline, the authors review epistemological perspectives and methodological advances in anthropology and psychology. Thus informed, they both summarize and critique constructivist and positivist approaches to knowledge development and practice that cross or resist the crossing of cultures. The authors outline a multicultural collaborative research method that supports extending and refining the profession’s knowledge in a way that both honors local perspectives and reveals concepts that cross cultures. Insights from a study that explored the meaning of food preparation to older Thai, American, and New Zealand women provide illustrative examples.