Whooping cough (pertussis) caused by B. pertussis (B.p) is still serious public health threat. B. parapertussis (B.pp), closely related to B.p, also causes whooping cough. The incidence of B.pp infections has been increasing over the last decades, partly because pertussis vaccines have low efficiency against B.pp infections. Moreover, because the majority of pertussis patients are infants, common antimicrobial agents producing serious adverse reactions in infants are not fully satisfactory. Therefore, we try to identify potential vaccine candidates and alternative drug targets against both B.p and B.pp. This preliminary work integrates several different kinds of data from in silico analysis, comparative genomic hybridization, global transcriptional profiling, and protein-protein interaction (PPI) network to screen potential vaccine candidates and drug targets against the two species. Finally, 191 potential crossprotective vaccine candidates are identified. They have high transcriptional levels in both species, or are associated with virulence and pathogenesis. Moreover, these proteins are not only potentially surface-exposed in the bacteria, but also well conserved among the 165 B.p and B.pp strains. Among them, 22 candidates with high essentiality in the two PPI networks of B.p and B.pp are regarded as suitable drug targets against the two species. We just selected Bordetella as an example to develop a rapid and reliable approach for screening alternative drug targets that associated with novel protein pathways, complexes, and cellular functions against these antibiotic-resistant pathogens. Further researches focusing on the 191 vaccine candidates could accelerate the development of more effective vaccines and drug therapy against B.p and B.pp infection.