In budding yeast, the non-essential subunit of DNA polymerase delta POL32 is required for break-induced replication (BIR), a specialized form of homologous recombination (HR) for DNA double-strand break repair, when one of the broken DNA fragments is missing. Since the DNA lesions, on which BIR acts, resemble collapsed DNA replication forks and since collapsed forks are prevalent in human cancers, we examined whether depletion of POLD3, the human ortholog of POL32, impairs DNA replication in cancer cells. In cells overexpressing cyclin E, depletion of POLD3 or POLD4, another subunit of DNA polymerase delta, induced the accumulation of prematurely-terminated forks and inhibited cell cycle progression. However, in the absence of oncogene-induced DNA replication stress, POLD3 or POLD4 depletion had no effect on DNA replication fork dynamics or cell proliferation. POLD3 and POLD4 were also not involved in the response of cells to DNA replication stress induced by hydroxyurea or aphidicolin. We propose that BIR is relevant in higher eukaryotes and mediates repair of the collapsed DNA replication forks present in human cancers.