Among the large number of possible antisense species against a given target RNA, only a small number shows effective suppression of the target gene in living cells. In the case of short-chain antisense oligonucleotides (asON) which usually comprise less than approximately 25 nucleotides, local structures of the target RNA seem to be of particular importance for the extent of gene suppression. Experimental approaches to identify promising local target sequences and, hence, complementary asON sequences, have provided tools to define asON that are biologically active at higher than statistical probability. However, experimental protocols are expensive, time consuming, and are associated with intrinsic basic and technical limitations. As insights into the structure-function relationship of asON as well as the role of sequence motifs increase, it becomes feasible to consider computer-based theoretical approaches for the design of effective asON. In the following we describe how individual steps of the theoretical design of asON may be automated by establishing and implementing suitable algorithms.