Embodiments of the present invention relate to multicistronic vectors and methods for their design. Methods and compositions of the invention include a vector including at least two cistrons, wherein a first cistron includes a first promoter and a first nucleic acid sequence encoding one or more therapeutic agents, and wherein a second cistron comprises a second promoter and a second nucleic acid sequence encoding one or more RNA molecules that interfere with the expression of a biological response modifier or the therapeutic agent, wherein the expression of the first sequence is under control of the first promoter and expression of the second sequence is under control of the second promoter.