The multidrug resistance of numerous pathogenic microorganisms is a serious challenge that raises global healthcare concerns. Multi-target medications and combinatorial therapeutics are much more effective than single-target drugs due to their synergistic impact on the systematic activities of microorganisms. Designing efficient combinatorial therapeutics can benefit from identification of synthetic lethals (SLs). An SL is a set of non-essential targets (i.e., reactions or genes) that prevent the proliferation of a microorganism when they are “knocked out” simultaneously. To facilitate the identification of SLs, we introduce Rapid-SL, a new multimodal implementation of the Fast-SL method, using the depth-first search algorithm. The advantages of Rapid-SL over Fast-SL include: (a) the enumeration of all SLs that have an arbitrary cardinality, (b) a shorter runtime due to search space reduction, (c) embarrassingly parallel computations, and (d) the targeted identification of SLs. Targeted identification is important because the enumeration of higher order SLs demands the examination of too many reaction sets. Accordingly, we present specific applications of Rapid-SL for the efficient targeted identification of SLs. In particular, we found up to 67% of all quadruple SLs by investigating about 1% of the search space. Furthermore, 307 sextuples, 476 septuples, and over 9000 octuples are found for Escherichia coli genome-scale model, iAF1260.