The dissemination of antibiotic resistance among pathogenic bacteria can be attributed largely to conjugative DNA transfer. The general category of conjugative transfer includes both bacterial plasmid conjugation and the transfer of nonreplicative conjugative transposons. Prototypes for these two systems are the plasmid RK2 and the conjugative transposon Tn916. To address the long-term problem of the increasing prevalence and severity of antibiotic resistance, strategies aimed against conjugative transfer are needed, but their development will require a greater understanding of conjugative resistance gene acquisition. Overviews of the two conjugative transfer systems are presented, to summarize and compare current concepts. Observations regarding transfer of conjugative transposons is consistent with the prevailing model for plasmid conjugation, that is, by the transfer of a single-stranded DNA molecule from the donor to the recipient bacterium, and the generation of the single strand by rolling circle DNA replication. The relevance of vegetative plasmid replication and host range to the spread of multiple drug resistance is discussed, and clinical examples of conjugative transfer of multiple antibiotic resistance illustrate the severity of the current situation. Possible directions, traditional and innovative, are offered to address the conjugative transfer problem in drug resistance, and potentially to break the cycle of antibiotic development followed by the bacterial resistance gene acquisition.