Inspired by the vision of the Millennium Declaration, CARE and ICRW (International Centre for Research on Women) partnered with the Inner Spaces, Outer Faces Initiative (ISOFI) to learn how to more effectively integrate gender and sexuality into CARE's sexual and reproductive health programmes. Drawing from lessons learned from gender mainstreaming, ISOFI focuses initially on fostering personal change among staff, helping them to explore their own gender and sexuality 'baggage' and supporting transformation of their 'inner space'. ISOFI then gradually integrates mechanisms to promote organizational change, and finally extends to community development practice, the 'outer face'. As a system promoting change in organizational culture and practice, ISOFI features structured iterative loops of reflection and learning, action and experimentation, and analysis and assimilation. This article describes the ISOFI Innovation System, and reports on ISOFI-generated learning and innovation in sex positive HIV prevention programming for truckers and reproductive health interventions for women in India.