This commentary outlines the theoretical underpinnings of Cultural-Historical Activity Theory (CHAT) and demonstrates its application to pharmacy practice. CHAT offers a comprehensive framework to address the complex challenges faced by pharmacists in an ever-evolving healthcare environment. CHAT provides pharmacy researchers with a different way of approaching and addressing practice research problems that appear to be resistant to traditional methods that may focus on cause and effect. This commentary introduces five of CHAT's foundational concepts: learning, activity, systems, culture, and change. CHAT emphasizes collective learning and the transformative potential of viewing contradictions within pharmacy practice as opportunities for innovative solutions and systemic change. By applying CHAT, pharmacists are encouraged to engage in the holistic examination of their work environments to address persistent problems and concerns. An application of CHAT in pharmacy is provided through an example where tensions arising from the introduction of electronic patient records and electronic prescribing systems were examined. This analysis shows how systemic contradictions can be leveraged to enhance pharmacist practice. A CHAT-informed solution differs from offering recommendations that involve individual-focused training to one that encompasses a wider professional development approach. By focusing on expansive learning and the co-creation of new practice models, CHAT provides a robust theoretical foundation for rethinking pharmacy practices in response to the complexities of contemporary healthcare.