The BRCA1 Carboxy-Terminal (BRCT) tandem domains are present in several proteins (e.g., NBN, BRCA1, and MDC1) involved in the response to the DNA double-strand breaks (DSBs) sensing and signaling. These domains are pivotal in phosphorylation-dependent protein-protein recognition, and epidemiological data indicate a relationship between mutations within BRCT domains and cancer susceptibility. Human nibrin (NBN) forms a trimer with MRE11 and RAD50 (MRN complex) involved in nearly every aspect of DNA damage response (DDR), including sensing, signaling, and repair of DNA lesions. In mammalian cells, the histone H2AX represents a crucial component of the DDR. In fact, in response to DSB induction, H2AX is phosphorylated at the Ser139 residue (the phosphorylated H2AX protein being named γ-H2AX), serving as a platform for the assembly of proteins involved in DNA repair and checkpoint response, like NBN, BRCA1, and MDC1. To date, the exact role of BRCT domains of NBN in all the phases of the DDR is still a matter of debate, and controversial data are available regarding protein-protein recognition and timing of BRCT-containing proteins localization on the DSB. Indeed, while some authors demonstrated that NBN can directly interact by its tandem BRCT domains with γ-H2AX, others suggest that tandem BRCT domains of NBN mediate the interaction with phosphorylated MDC1, rather than with γ-H2AX. Here, structural and functional aspects of NBN recognition by either γ-H2AX or MDC1 are discussed to shed light on timing of BRCT-containing proteins localization on the DSB.