The nuclear factor κB (NF-κB) plays an important role in tumorigenesis by affecting processes such as tumor initiation, promotion, growth, and metastasis. NF-κB induces the expression of genes that are known to confer resistance to apoptosis. Therefore, its activation has been associated with the development of chemo- and radiation resistance in cancer cells. NF-κB is constitutively activated in many types of tumor cells by mechanisms that are not well understood. Like NF-κB, tissue-type transglutaminase (TG2), the most diverse and ubiquitous member of the calcium-dependent transglutaminase family of enzymes, is also aberrantly overexpressed in many human cancer types, blocks apoptosis, and promotes drug resistance and metastatic phenotypes. In this review, we will discuss the current understanding of the mechanisms thought to participate in constitutive activation of NF-κB. Particular focus is given to the implications of increased TG2 expression in NF-κB activation and its contributions to the development of drug resistance and metastatic phenotypes in cancer cells.