We reviewed the Spanish translation of the Youth Quality of Life Instrument-Research Version (YQOL-R) and culturally adapted the measure with Puerto Rican and Mexican American children and adolescents. The YQOL-R is a self-reported measure that includes four domains: Sense of Self, Social Relationships, Environment, and General Quality of Life. A total of 10 focus groups were conducted with children aged 9 to 11, adolescents aged 12 to 17, their parents, and mental health providers. Five focus groups were conducted in San Diego, California and five in San Juan, Puerto Rico. Eligible participants were recruited from children's outpatient psychiatry clinics. We followed an iterative and recursive process in reviewing changes and modifications to the instrument using a bilingual committee and a Multi National Bilingual Committee. Greater semantic, content, and technical equivalence of the Spanish and English versions for the YQOL-R was achieved for the two largest U.S. Latino subgroups: Mexican Americans and Puerto Ricans. The cultural adaptation process revealed several important issues regarding the measurement of quality of life in different age groups. Additional items for school, relationships (both family and friends) and spare time suggested the need for a future children's version of the instrument. For the adolescents, additional items were suggested in the areas of sexuality, intergenerational conflict and acculturative stress.