The evidence that cancer development is a complex and multistep process, characterized by alterations of genes involved in the regulation of proliferation, apoptosis and angiogenesis, has led to development of new therapeutic strategies based on the use of agents able to selectively inhibit key molecules of these pathways. In particular, antisense oligonucleotides (ASOs) have proved their efficacy as targeted therapy in preclinical studies, have been well tolerated and able to modulate target protein expression in clinical studies. Although these agents have shown considerable promise for antitumoral therapy, treatment with ASOs used as single agent does not seem particularly promising because of the multigenic alterations of tumors. Based on these considerations, approaches based on the combination of ASOs targeting oncogenes involved in different molecular pathways have been investigated. Moreover, the role of this novel strategy when integrated with conventional drugs or signaling inhibitors, has been assessed. This review addresses some advances in the ASOs combination and reports the potential application of this strategy for the treatment of human cancer.