Recombinant adenoviruses that selectively replicate in E2F deregulated tumor cells are described. The recombinant adenoviruses have a genome encoding a modified E1A protein, a modified or deleted E4orf1 protein, a modified or deleted E4orf6/7 protein, or any combination thereof, such that the recombinant adenoviruses exhibit replication defects in normal cells compared to tumor cells. In some instances, the recombinant adenovirus genomes encode additional modifications that target the recombinant adenoviruses to specific cell types, detarget the viruses from the liver, inhibit viral replication in the liver, and/or evade pre-existing neutralizing antibodies.