Since the first attempts to understand the mechanisms of learning, memory, development, and other instances of neuroplasticity, gene expression has been an attractive explanation for the persistence of such processes. It has been hypothesized that changes in the levels of expression of a gene, or a coordinated set of genes, would be necessary for dramatic structural changes like the growth of new neurites. And more subtle biochemical changes at existing synapses might also result from an alteration in the array of gene products being manufactured in the relevant cells. However, a great deal of what is classified as neuroplasticity is dependent on primary changes in electrophysiological activity or other conditions at synapses. Therefore, a seminal question to those interested in the molecular underpinnings of neuroplasticity is that of signal transduction: How do changes in synaptic activity get communicated to the nucleus? To many who learn about the regulation of the transcription factor NFkappaB with this question in mind, its utility seems clear. Furthermore, NFkappaB is an important signaling factor for cytokines that appear to participate in several pathological conditions (e.g., Parkinson's disease, multiple sclerosis, and depression), so understanding its mechanisms of action and its relationship to other elements of cytokine signaling may be fundamental to determining the role of the inflammatory system in psychiatric and neurodegenerative conditions. For these reasons, NFkappaB has garnered considerable attention in various aspects of neuroplasticity, from long-term potentiation to the most dramatic forms of plasticity: cell birth and death. In a few cases, elegant experimental design has resulted in convincing evidence for the involvement of NFkappaB in specific phenomena. However, the complexity of this transcription factor-including confusion over what exactly is meant by "NFkappaB"-has led to some misleading conclusions, as well. This chapter highlights some of the potential red herrings to be encountered in the study of NFkappaB and will summarize the data and interpretations in which some degree of confidence can be placed. The final answers will depend on the application of models and tools only now in development.