Contagious bovine pleuropneumonia (CBPP) remains a major cattle disease in Africa with serious socio-economic consequences. Its eradication requires the development of improved vaccines. Knowledge on this disease and its causing agent, Mycoplasma mycoides subsp. mycoides biotype Small Colony (MmmSC), has been progressing significantly in the last years, opening new areas for vaccine design. Advances were achieved in the understanding of the protective immune responses to MmmSC infection and immunopathological mechanisms allowing the pathogen to escape the host immune response. Based on sequencing and genomic studies, some virulence factors and metabolic pathways were unraveled leading to the identification of potential MmmSC vaccine candidates. Based on these findings, this review presents a scientific strategy to design multi-component sub-unit vaccines for mucosal delivery as the most promising approach for efficient long-term protective vaccines to prevent CBPP.