The transcription factor NF-κB, a homodimeric or heterodimer consisting of five proteins, has an important function in regulating immune response, cell differentiation, apoptosis and tumorigenesis. As one subunit of NF-κB, RelA contains various post-translational modifications (PTMs), including phosphorylation, acetylation, methylation, ubiquitination etc. The PTMs could subtly regulate the activity and function of NF-κB in response to diverse stimuli in different cell types. They had distinct function and the same modification could result in different influences depending on the context. In addition, there are complicated mutual effect between different modifications, sometimes antagonistic and sometimes synergistic. In consideration of the importance of NF-κB in human health, understanding these modifications will not only provide valuable insights into the regulation mechanism of NF-κB pathway, but also lead to new drug targets and diagnostic biomarkers for related disease.