The lymphomagenic action of myc genes in conjunction with Epstein‐Barr virus nuclear antigen‐1 (EBNA‐1) have been examined using transgenic mice in several separate tests. Synergy between Myc and EBNA‐1 in lymphomagenesis was revealed in a cross breed study where co‐expression of transgenic myc and EBNA‐1 led to a tumor latency period reduced significantly in some crosses. In the resulting bitransgenic tumors, expression of the Eμ‐myc genes was not affected by EBNA‐1 expression. MoMLV was utilized as a transposon tag to activate cellular oncogenes by infection of EμEBNA‐1 mice. Rearrangement at the c‐myc locus in B cell tumors from these mice again suggests a cooperative action between myc and EBNA‐1. Tumors arising in EμEBNA‐1 mice typically showed a trisomy of chromosome 15, upon which the c‐myc locus resides. Bitransgenic tumors (EBNA‐1/c‐myc) did not show trisomy 15. This raises the possibility that amplification of c‐myc is factorial in the selection of trisomy 15 in these tumors. These data indicate that myc and EBNA‐1 act cooperatively and are not redundant in lymphomagenesis. Expression of EBNA‐1 by EBV may provide a selection pressure in addition to translocation of the c‐myc locus in the genesis of endemic Burkitt's lymphoma (BL). © 2003 Wiley‐Liss, Inc.