The goal of this longitudinal analysis was to characterize factors associated with the experience of life stress in low-income, inner-city mothers of minority children with high-risk asthma.Participants (n = 276) reported on family demographics, child asthma control and healthcare utilization, social support, contemporary life difficulties (housing, finances, violence exposure) measured by the validated Crisis in Family Systems scale, and daily stress. Latent growth curve modeling examined predictors of life stress across 12 months as a function of home and community difficulties, asthma-specific factors, and social support. Mothers were primarily single (73%), unemployed (55%), and living in extreme poverty with most (73%) reporting an annual family income <$20,000 (73%). The children were young (mean age = 5.59, SD = 2.17), African-American (96%), and had poorly controlled asthma (94%) at study enrollment. Higher daily stress was associated with financial difficulties, safety concerns in the home and community, and housing problems. Access to social support was consistently related to reduced stress. The only asthma-specific factor associated with life stress was healthcare utilization, with more emergency services for asthma related to higher daily stress. Findings underscore the clinical significance of assessing diverse home and community stressors and social support in low-income, inner-city caregivers of children with poorly controlled asthma.