The innovation landscape in many African economies is changing dramatically. However, up to date, few empirical knowledge exists on how domestic firms operate in this changing environment. This (explorative) chapter aims to contribute to a more nuanced picture on innovation and successful entrepreneurship in African economies by presenting some cases of innovative entrepreneurs and start-ups in Kenya and Nigeria, which are exemplary for a new generation of companies started and managed by African entrepreneurs. The chapter specifically looks into the determinants of their success. Internal determinants for success include the level of education of the founding entrepreneurs, the registration and formalization of the company, access to capital, an entrepreneurial spirit and attitude among the founders of the firms, and effective and innovative use of available new technologies, in particular ICT. External determinants include and an emerging middle class of consumers, and both countries being leading regional innovation hubs and major entry points for investors and companies who aim to serve regional markets in West and East Africa. This conducive environment creates business opportunities for local start-ups and growth oriented local firms.