Nuclear factor-κβ (NF-κB) binds specifically to NF-κB-binding sites (κB sites, 5′-GGGRNNYYCC-3′; R, purine; Y, pyrimidine; N, any nucleotide) present in enhancer regions of various genes. Binding of various cytokines, growth factors and pathogen-associated molecular patterns to specific receptors activates NF-κB and expression of genes that play critical roles in inflammation, innate and acquired immunity, bone remodeling and generation of skin appendices. Activation of NF-κB is also involved in cancer development and progression. NF-κB is activated in cells that become malignant tumors and in cells that are recruited to and constitute the tumor microenvironment. In the latter scenario, the TLR-TRAF6-NF-kB pathways seem to play major roles, and NF-κB activation results in production of cytokines, which in turn induce NF-κB activation in premalignant cells, leading to expression of genes involved abnormal growth and malignancy. Furthermore, NF-κB activation is involved in bone metastasis. Osteoclasts, whose generation requires the RANK-TRAF6-NF-κB pathways, release various growth factors stored in bone, which results in creation of microenvironment suitable for proliferation and colonization of cancer cells. Therefore, NF-κB and molecules involved its activation, such as TRAF6, are attractive targets for therapeutic strategies against cancer.