Hydroxyurea (HU) is a simple organic compound currently used as a cancer chemotherapeutic agent. It acts specifically on the S-phase of the cell cycle by inhibiting the enzyme ribonucleoside diphosphate reductase, thereby hindering the reductive conversion of ribonucleotides to deoxyribonucleotides and thus limiting de novo DNA synthesis. HU is employed in hemotological settings as a first-line treatment of myeloproliferative disorders, such as polycythemia vera, essential thrombocythemia and primary myelofibrosis, apart from having a vital role in combination therapy for management of malignant melanoma, head and neck cancers and brain tumors. It offers an advantage that the patient may take this drug on an ambulatory basis with minimum clinical toxicity, while some of its limitations include gastrointestinal disturbance and bone marrow depression. This review will summarize and present the overall effects of HU and its combination therapy as an anticancer agent.