Fighting cancer is considered one of the most important areas of research in medicine and immunology. Due to the ability of cancer cells to mutate and become resistant to available drugs, new scientific approaches, focused on molecular mechanisms of carcinogenesis, are needed. A new direction in cancer treatment has arisen, devoted to the adjuvant use of natural bioactive compounds in conventional chemotherapy. This kind of research is gaining more attention. In particular, fungi can be used not only as strong immunoceuticals but also as a source of potent metabolites, capable of penetrating cell membranes and interfering with particular signal transduction pathways linked to processes such as inflammation, cell differentiation and survival, carcinogenesis, and metastasis. One such a crucial pathway involved in the above-mentioned processes, is the activation of the nuclear transcription factor kappaB (NF-kappaB). This review compiles the available data on fungal metabolites, known to modulate the activity of NF-kappaB, thus demonstrating their potential use as novel anti-cancer agents in the rapidly advancing field of molecular therapy.