Most cancer therapies are seldom effective by using one anticancer drug owing to refractory and resistance property of cancer tissues caused by multiple genetic alterations and molecular abnormalities. Despite great popularity of anticancer drug combination utilizations, the hidden rules behind scenarios emerge in new era of anticancer therapy. Most importantly, anticancer drug cocktails need to transform from empirical to science-guided enterprises. This editorial offers the background knowledge of drug combination therapy across the history. Possible future landscapes and drawbacks of current cancer drug combinative therapy are addressed and speculated.