DNA helicases have historically been implicated in the initiation or elongation phases of DNA replication; however, elegant studies in prokaryotic systems have suggested more specialized functions of helicases to stabilize the replication fork when DNA replication is impeded. More recently, it has become increasingly evident that eukaryotic DNA helicases function at replication forks to participate in processes that include DNA damage detection and signaling, resolution of alternate DNA structures, fork regression, and replication restart. Genetic and biochemical studies have begun to elucidate the molecular roles of DNA helicases at the replication fork in the coordination of the synthesis and processing of leading and lagging strand, a vital function to preserve genomic integrity. In addition, ATP-dependent chromatin remodeling by helicase-like proteins during replication initiation, elongation, or restart may have important roles as well. These themes will be discussed with an emphasis on the cellular mechanisms of DNA helicases/chromatin remodeling enzymes implicated in human disease and proposed to function with other protein factors during replication.