This chapter articulates a practice-oriented critical vision of cultural differences to global design and explores how we should productively engage differences in global design practices. Cultural differences in this book refer to the differences that emerge from various categorical identifications such as ethnicity, race, age, class, religion, gender, sexuality, and ability and manifests as ways of life. A practice-oriented critical vision sees cultural differences as dynamic, relational, emergent, contingent, and liminal, in contrast to a simplistic interpretation of cultural differences presented by multiculturalism and other theories. This chapter first reviews why cultural differences matters and then organizes the discussion around four sets of questions: First, how does difference come into being? Second, what is the nature of difference ontologically? Third, how should we treat difference methodologically and practically? Fourth, as designers, how can we turn differences into design resources? And how should we design with, across, and for cultural differences? Based on the articulation of a practice-oriented critical vision of differences that turns communication deficits into design resources, the culturally localized user experience (CLUE) approach is thus developed into the approach of culturally localized user engagement and empowerment (CLUEE), simplified as the CLUE2 (CLUE-squared) approach. Examples of race construction and social media design cases are provided to enrich the discussion.