Even when markets become more accessible to poor people in general, wealth differentials occur and the most vulnerable are the ones excluded. The reasons for their exclusion are complex and inextricably linked with many aspects of their lives; an integrated approach takes these multiple dimensions of poverty into account, whilst addressing their deep levels of poverty through employment and enterprise. This article focuses on reaching those who are excluded from markets due to pervasive social discrimination and other challenges specific to their disability and health context. Two case studies of people with disabilities and those affected by HIV/ AIDS describe entry points and key services required to facilitate and sustain their participation as employees and enterprise owners. They demonstrate how successful models use participation in economic activities to achieve sustainable impact through stimulating attitude change, and create a more level playing field for their access to markets and wider development processes.