Understand perceived barriers to and facilitators of using clinical informatics applications for pharmacogenomic (PGx) implementation in resource-limited settings. We conducted a qualitative research study using a semi-structured interview guide informed by the Consolidated Framework for Implementation Research (CFIR). Interview questions assessed CFIR contextual determinants related to: electronic health record (EHR) infrastructure; clinical informatics personnel and resources; EHR integration of PGx test results; PGx clinical decision support (CDS) tools; institutional resources; and partner receptivity. Transcripts were coded and analyzed to identify themes. We interviewed 24 clinical informaticists and executive leaders working in rural or underserved health care settings in Montana (n = 15) and Colorado (n = 9) and identified three major themes: (1) EHR infrastructure limitations, (2) insufficient supporting resources, and (3) unique contextual considerations for resource-limited settings. EHR infrastructure limitations included limited agency related to EHR build and interoperability concerns. Theme 1 highlighted challenges associated with integrating structured data into the EHR and inadequate vendor support. Theme 2 included limited familiarity with PGx across the care team, cost concerns, and allocation of non-financial resources. Theme 3 highlighted perceptions about the clinical utility of PGx within rural and underrepresented populations. Potential facilitators, such as being able to act nimbly, were found to coexist among the reported barriers. Our results provide insight into the clinical informatics infrastructure in resource-limited settings and identify unique considerations for clinical informatics-facilitated PGx implementation. Future efforts in these settings should consider innovative partnerships and strategies to leverage facilitators and minimize barriers associated with integrating PGx CDS applications.