AbstractBackground: The p55 family WD40 repeat‐containing histone chaperone proteins are components of several chromatin regulatory complexes (such as PRC2, NURF and CAF‐1) and interact with histone H4, yet their functional relevance in vivo is unclear. Results: Here we use Drosophila as a genetic model to dissect the function of p55/Caf1 during development. In agree with a recent report, we find that p55 is essential for Drosophila development and is required for cell proliferation and viability. However, our data further demonstrate that histone H3K27 di‐/tri‐methylation and PRC2‐mediated gene silencing still occur normally when p55 is missing. p55 is also implicated in bridging chromatin regulatory complexes to the chromatin by binding to histone H4, but we find that a transgene of p55 whose binding pocket is disrupted could still functionally substitute the wild‐type p55 for the survival. Conclusions: Our studies suggest that p55 is not crucial for PRC2‐mediated gene silencing in vivo, and the vital function of p55 is probably not dependent on its interaction with histone H4. Developmental Dynamics 241:455–464, 2012. © 2012 Wiley Periodicals, Inc.