Cyanobacteria of the genera Synechococcus and Prochloroccocus and the viruses that infect them are abundant in the marine environment. Coexistence between them is thought to be facilitated by the presence of both resistant and susceptible cells. While extracellular resistance by alterations in receptors is established, known intracellular defense mechanisms are lacking in these cyanobacteria. In order to investigate whether intracellular resistance exists in Prochlorococcus and Synechococcus we sought to identify infections that are halted inside the cell. We found that generalist T4-like cyanophages tend to adsorb to resistant hosts more often than specialist phages. We next tested DNA expression and replication of generalist and specialist phages inside resistant strains. This revealed that viral RNA of generalists, but not of a specialist, was expressed. In addition, the genome of generalists was replicated in one of the resistant Synechococcus strains. These data indicate that resistance to broad-host-range phages is often conferred inside the cell and may be due to novel intracellular mechanisms of defense.