Among the large number of possible antisense oligonucleotides (asODN) against a given target nucleic acid, only a small number of species seems to give rise to satisfactorily strong inhibition of target gene expression in living cells. Therefore much attention is paid to strategies that help to successfully design effective asODN. Here, selected experimental approaches and theoretical concepts will be briefly described that have been developed to increase the probability of success in the use of asODN. Advantages and disadvantages of these strategies will be compared and the relatively new and controversially discussed concept of a theoretical and computer-supported design of effective asODN will be addressed.