Translesion synthesis (TLS) DNA polymerases were originally described as error-prone enzymes involved in the bypass of DNA lesions. However, extensive research over the past few decades has revealed that these enzymes play pivotal roles not only in lesion bypass, but also in a myriad of other cellular processes. Such processes include DNA replication, DNA repair, epigenetics, immune signaling, and even viral infection. This review discusses the wide range of functions exhibited by TLS polymerases, including their underlying biochemical mechanisms and associated mutagenicity. Given their multitasking ability to alleviate replication stress, TLS polymerases represent a cellular dependency and a critical vulnerability of cancer cells. Hence, this review also highlights current and emerging strategies for targeting TLS polymerases in cancer therapy.