BACKGROUND: The importance of strong and transformative leadership is recognised as essential to the building of resilient and responsive health systems. In this regard, Sustainable Development Goals (SDG) 5 prioritises a current gap, by calling for women's full and effective participation and equal opportunities for leadership, including in the health system. In South Africa, pre-democracy repressive race-based policies, coupled with strong patriarchy, led to women and especially black women, being 'left behind' in terms of career development and progression into senior health leadership positions. METHODS: Given limited prior inquiry into this subject, we conducted a qualitative exploratory study employing case study design, with the individual managers as the cases, to examine the influence of gender on career progression and leadership perceptions and experiences of senior managers in South Africa in five geographical districts, located in two provinces. We explored this through in-depth interviews, including life histories, career pathway mapping and critical incident analysis. The study sample selection was purposive and included 14 female and 5 male senior-managers in district and provincial health departments. RESULTS: Our findings suggest that women considerably lag behind their male counterparts in advancing into management- and senior positions. We also found that race strongly intersected with gender in the lived experiences and career pathways of black female managers and in part for some black male managers. Professional hierarchy further compounded the influence of gender and race for black women managers, as doctors, who were frequently male, advanced more rapidly into management and senior management positions, than their female counterparts. Although not widespread, other minority groups, such as male managers in predominantly female departments, also experienced prejudice and marginalisation. Affirmative employment policies, introduced in the new democratic dispensation, addressed this discriminatory legacy and contributed to a number of women being the 'first' to occupy senior management positions. In one of the provinces, these pioneering female managers assumed role-modelling and mentoring roles and built strong networks of support for emerging managers. This was aided by an enabling, value-based, organisational culture. CONCLUSION: This study has implications for institutionalising personal and organisational development that recognise and appropriately advances women managers, paying attention to the intersections of gender, race and professional hierarchy. It is important in the context of national and global goals, in particular SDG 5, that women and in particular black women, are prioritised for training and capacity development and ensuring that transformative health system policies and practices recognise and adapt, supporting the multiple social and work roles that managers, in particular women, play.