Human cells contain various repetitive DNA sequences, which can be a challenge for the DNA replication machinery to travel through and replicate correctly. Repetitive DNA sequence can adopt non-B DNA structures, which could block the DNA replication. Prolonged stalling of the replication fork at the endogenous repeats in human cells can have severe consequences such as genome instability that includes repeat expansions, contractions, and chromosome fragility. Several neurological and muscular diseases are caused by a repeat expansion. Furthermore genome instability is the major cause of cancer. This chapter describes some of the important classes of repetitive DNA sequences in the mammalian genome, their ability to form secondary DNA structures, their contribution to replication fork stalling, and models for repeat expansion as well as chromosomal fragility. Included in this chapter are also some of the strategies currently employed to detect changes in DNA replication and proteins that could prevent the repeat-mediated disruption of DNA replication in human cells. Additionally summarized are the consequences of repeat-associated perturbation of the DNA replication, which could lead to specific human diseases.