Purpose: Clinical innovation—where doctors develop and use novel interventions that differ from standard practice and that have not been shown to be safe or effective—has the potential to transform patient care and advance medical practice. However, it is not without risk. To encourage responsible clinical innovation, healthcare institutions need to understand what drives and deters doctors from developing and using innovative interventions. While existing research has provided valuable insights into contextual factors (e.g. resource constraints), less attention has been paid to individual factors (e.g. individual traits). Methodology: The aim of this qualitative study was to investigate the factors that drive and deter clinical innovation across diverse medical specialties. Thirty-one semi-structured interviews were conducted with Australian surgeons, fertility specialists and cancer care physicians. Results: We found that a combination of individual traits (e.g. curiosity), interests (e.g. obligations to patients, and financial concerns) and contextual factors were perceived to converge and synergistically influence doctors’ use of innovative interventions. Conclusion: Our findings suggest that while addressing structural barriers to clinical innovation at the health system level remains important, attention must also be given to the interests of physician-innovators and other stakeholders including patients, healthcare institutions, and industry. Understanding these interests, the complex ways in which they align and conflict, and the ways in which they intersect with contextual factors and individual traits will enable healthcare institutions to encourage physician-led innovation and ensure that it is responsible.