Gain-of-function mutations had been believed to function as a single mutation in oncogenes, although some secondary mutations, such as EGFR T790M mutations, are frequently acquired in patients that are resistant to tyrosine kinase inhibitor treatment. Recently, we and other investigators have reported that multiple mutations (MMs) frequently occur in the same oncogene before any therapy. In a recent pan-cancer study, we identified 14 pan-cancer oncogenes (such as PIK3CA and EGFR) and 6 cancer type-specific oncogenes that are significantly affected by MMs. Of these, 9% of cases with at least one mutation have MMs that are cis-presenting on the same allele. Interestingly, MMs show distinct mutational patterns in various oncogenes relative to single mutations in terms of mutation type, position, and amino acid substitution. Specifically, functionally weak, uncommon mutations are overrepresented in MMs, which enhance oncogenic activity in combination. Here, we present an overview of the current understanding of oncogenic MMs in human cancers and provide insights into their underlying mechanisms and clinical implications.