Cancer at various stages and therapy is observed in about 15% of patients with acute coronary syndrome (ACS). Current guidelines for invasive and conservative treatment of ACS cannot be applied to all patients with cancer. The choice of antiplatelet and anticoagulant drugs should be individualized with clopidogrel as a key P2Y12 inhibitor in this population. Major challenges of therapy in patients with ACS and cancer include limitations for the use of the recommended antithrombotic therapy (particularly in case of cancer-related thrombocytopenia or when anticoagulation is needed due to concomitant atrial fibrillation or venous thromboembolism), the management of bleeding complications, eligibility criteria for cancer surgery, and reinitiation of chemotherapy or radiotherapy after ACS. This review summarizes the current evidence and our own experience in the treatment of ACS in cancer patients. Since prognosis has considerably improved in many cancer patients in the last decade, optimal therapy of ACS may increase the life expectancy and reduce the risk of adverse coronary events after ACS in this high-risk population.