It has become increasingly clear that deregulation of the NFkappaB signaling cascade is a common underlying feature of many human ailments including cancers. The past two decades of intensive research on NFkappaB has identified the basic mechanisms that govern the functioning of this pathway but uncovering the details of why this pathway works differently in different cellular contexts or how it interacts with other signaling pathways remains a challenge. A thorough understanding of these processes is needed to design better and more efficient therapeutic approaches to treat complex diseases like cancer. In this review, we summarize the literature documenting the involvement of NFkappaB in cancer, and then focus on the approaches that are being undertaken to develop NFkappaB inhibitors towards treatment of human cancers.