The repair of DNA double strand breaks (DSBs) by the non-homologous end-joining pathway (NHEJ) is central for the proper development of the adaptive immune system. This repair pathway involves eight factors, including XRCC4-like factor (XLF)/Cernunnos and the paralog of XRCC4 and XLF, PAXX non-homologous end-joining factor (PAXX). Xlf-/- and Paxx-/- mice are viable and exhibit only a mild immunophenotype. However, mice lacking both PAXX and XLF are embryonic lethal because postmitotic neurons undergo massive apoptosis in embryos. To decipher the roles of PAXX and XLF in both V(D)J recombination and immunoglobulin class switch recombination (CSR), here, using Cre/lox-specific deletion to prevent the double-KO embryonic lethality, we developed two mouse models of a conditional Xlf KO in a Paxx-/- background. Cre expressed under the control of the iVav or CD21 promoter enabled Xlf deletion in early hematopoietic progenitors and splenic mature B cells, respectively. We demonstrate the XLF and PAXX interplay during V(D)J recombination in vivo, but not during CSR for which PAXX appeared to be fully dispensable. A Xlf/Paxx-double KO in hematopoietic progenitors resulted in a shorter lifespan associated with the onset of thymic lymphomas, revealing a genome caretaking function of XLF/PAXX.