•PWWP domains have strong binding affinity to histone lysine modified nucleosome.•PWWP domain proteins are associated with chromatin in a PWWP-dependent manner.•The PWWP domain is involved in crosstalk between different epigenetic marks.•Mutations in the PWWP domain have been linked to various human diseases. PWWP domain-containing proteins are often involved in chromatin-associated biological processes, such as transcriptional regulation and DNA repair, and recent studies have shown that the PWWP domain specifies chromatin localization. Mutations in the PWWP domain, a 100–150 amino acid motif, have been linked to various human diseases, emphasizing its importance. Structural studies reveal that PWWP domains possess a conserved aromatic cage for histone methyl-lysine recognition, and synergistically bind both histone and DNA, which contributes to their nucleosome-binding ability and chromatin localization. Furthermore, the PWWP domain often cooperates with other histone and DNA ‘reader’ or ‘modifier’ domains to evoke crosstalk between various epigenetic marks. Here, we discuss these recent advances in understanding the structure and function of the PWWP domain.