Rationale: Undocumented Mexican immigrants (UMIs) and their families make up a considerable proportion of the United States (U.S.) population at-risk for psychological distress. Yet, research to inform the mental health of UMIs is scant and existing studies often lack scientific rigor. This study used the Socio-Ecologic Framework and the Minority Stress Model, as well as context-sensitive methodology and Respondent Driven Sampling (RDS) to identify the prevalence of psychological distress, mental health disorders, and relevant Cultural and Contextual Concepts of Distress, among UMIs living in high-risk neighborhoods near the California-Mexico border region. Design: This study was a multi-stage project that included formative research, pilot testing, and a cross-sectional study that used Respondent Driven Sampling (RDS) as a sampling and data analysis methodology. Data for the RDS study was obtained from clinical interviews with 248 UMI adults of Mexican origin residing in North San Diego County. Primary mental health outcome measures included the Mini International Neuropsychiatric Interview (M.I.N.I.), the Brief Symptom Inventory (BSI-53), and the Bradford Symptom Inventory (aBSI). An adapted version of the Diagnostic and Statistical Manual for Mental Disorders (DSM) 5th Edition Cultural Formulation Interview (CFI) was used for the assessment of Cultural and Contextual Concepts of Distress. Results: Overall, 41% of UMIs met criteria for clinically significant psychological distress, with significant differences found for sex, age, and marital status. Additionally, 22% of UMIs met criteria for one or more mental health disorder based on DSM diagnosis, with the most prevalent disorders being Major Depressive Disorder (MDD: 14%) and Generalized Anxiety Disorder (GAD: 7%). Pertaining to Cultural Concepts of Distress, 24% of UMIs reported a lifetime prevalence of Nervios and 12% reported a lifetime prevalence of Ataque de Nervios, with the most common causal attributions for Nervios and Ataque de Nervios being family conflict (20%). Moreover, 82% of UMIs reported experiencing significant distress as a result of their undocumented status, which was found to be associated with significant migration-related loss, clinically significant psychological and somatic symptoms, and a negative effect on identity and self-esteem. Conclusions: UMIs are a population at risk of psychological distress given the multiple contextual stressors that these immigrants face. Debates on programs and policies pertaining to UMIs are complex and multifaceted, and divisiveness on immigration and welfare reform in the U.S. is long-standing. Tenacious grassroots efforts, both, in Mexico and in the U.S., are necessary to influence policy aimed to allocate funding to increase access to culturally and contextually responsive interventions aimed to address the complex mental health needs of this vulnerable population. It is the responsibility of both Mexico and the U.S. to work collaboratively in the development of programs and policies to prevent the negative consequences of inadequate access and to protect the human rights of Mexican immigrants looking for more promising futures.