The transcription factor nuclear factor (NF)-kappaB is activated in certain cancers and in response to chemotherapy and radiation. The transcriptional activation of genes associated with cell proliferation, angiogenesis, metastasis and suppression of apoptosis appears to lie at the heart of the ability of NF-kappaB to promote oncogenesis and cancer therapy resistance. Supporting these findings are recent experiments, performed in vitro and using xenograft models of cancer, which implicate NF-kappaB inhibition as an important new approach for the treatment of certain hematological malignancies and as an adjuvant approach in combination with chemotherapy or radiation for a variety of cancers. Clinical trials with drugs that block NF-kappaB are currently in progress with promising results. However, as there is currently no drug that blocks specific NF-kappaB activation, conclusions drawn with small-molecule inhibitors must be interpreted carefully.