Targeted cancer therapies represent a milestone towards personalized treatment as they function via inhibition of cancer-specific alterations. Polymerase θ (POLQ), an error-prone translesion polymerase, also involved in DNA double-strand break (DSB) repair, is often upregulated in cancer. POLQ is synthetic lethal with various DNA repair genes, including known cancer drivers such as BRCA1/2, making it essential in homologous recombination-deficient cancers. Thus, POLQ represents a promising target in cancer therapy and efforts for the development of POLQ inhibitors are actively underway with first clinical trials due to start in 2021. This review summarizes the journey of POLQ from a backup DNA repair enzyme to a promising therapeutic target for cancer treatment. POLQ is a versatile DNA repair enzyme that is central in TMEJ for the error-prone repair of DNA DSBs. POLQ also functions in other DNA repair pathways including base excision repair, interstrand crosslink repair, and DNA damage tolerance by translesion synthesis.Cancer cells often acquire mutations in DNA repair genes, making them dependent on remaining DNA repair pathways. Dependence on TMEJ is characterized by an increased POLQ expression which is associated with poor patient prognosis.Depletion of POLQ in POLQ-dependent cancers leads to synthetic lethality. This is well described for malignancies deficient in homologous recombination (e.g., due to mutations in BRCA1 or BRCA2). Hence, the use of POLQ inhibitors might be a promising strategy for targeted cancer therapy.