Cancers are characterized with altered genomes. Sequencing of thousands of cancer genomes has led to the identification of new types of complex genomic rearrangements that generate new chromosomes, known as chromoanagenesis. Chromothripsis is, to-date, the best characterized phenomenon of complex rearrangements, in which a single chromosome pulverization is followed by reassembly of broken DNA fragments in a random manner. Chromothripsis and chromothripsis-related events predominantly stem from mitotic- and post-mitotic aberrations, notably in consequence of chromatin bridges and micronuclei breakage. These mitotic defects result either from DNA breaks or from perturbations in the DNA replication program, leading to under-replication and DNA damage. In this chapter we describe the molecular mechanisms that connect replication stress to chromothripsis-related events. We focus on transcription-replication conflicts as a major source of endogenous replication stress.