Methamphetamine/amphetamine (MA)-related morbidity and mortality has been increasing in the United States. MA use is associated with high-risk sexual behavior and syringe-sharing practices. Homeless and marginalized housed persons (H/M) have high rates of substance use and mental health disorders. Little is known about trends of MA use among the H/M. The objective of this study was to quantify increases in MA use among H/M in San Francisco and to determine which demographic and behavioral subgroups have experienced the greatest increases in MA use. We conducted serial cross-sectional population-based studies in three waves: 1996–1997, 1999–2000, and 2003 and studied 2,348 H/M recruited at shelters and lunch lines. The main outcome was self-reported current (30-day) MA use. We found a tripling of current MA use among H/M persons from 1996 to 2003, with a sevenfold increase in smoked MA use. MA use doubled to tripled in most demographic and behavioral subgroups, whereas it quadrupled in those under age 35, and there was a fivefold increase among HIV-infected persons. The increase in MA use among H/M places a vulnerable population at additional increased risk for HIV infection and MA-use related morbidity and mortality. Among HIV-infected H/M, the increase in MA use has important public health implications for the development and secondary transmission of drug-resistant HIV caused by synergistic neurocognitive decline, poor adherence to HIV medications, and increased sexual risk behavior. Clinicians caring for H/M persons should inquire about MA use, refer interested MA users to MA dependence treatment programs and provide targeted HIV sexual risk reduction counseling. For HIV-infected H/M MA users, clinicians should closely monitor adherence to HIV or other chronic medications, to avoid unnecessary morbidity and mortality. Further research is needed to elucidate the most effective prevention and treatment for MA use and dependence among the H/M.