Cancer　is　a　leading　cause　of　death　in　both　developed　and　developing　countries.　Most　cancers　occur　as　a　result　of　somatically　acquired　alternations　in　the　genomes　of　normal　cells.　The　somatic　alterations　presented　in　a　cancer　genome　can　reach　about　ten　thousands.　However,　a　few　such　alterations　that　are　able　to　drive　initiation　and　progression　of　cancer　are　defined　as　＇driver＇　mutations,　while　all　other　mutations　are　assumed　to　be　randomly　acquired　and　termed　as　＇passenger＇　mutations.　Driver　mutations　confer　growth　advantage　on　the　cells　carrying　them　and　have　been　positively　selected　during　the　evolution　of　the　cancer.　Accumulating　driver　mutations　in　a　cell　genome　likely　result　in　multi-step　mutations　of　encoded　proteins　or　non-coding　transcripts,　which　change　their　biological　functions　of　the　proteins　and　transcripts.　Driver　mutations　potentially　have　been　classified　into　two　categories:　＇oncogenes＇　that　are　likely　resulted　from　gain-of-function　mutations　and　＇tumor　suppressor　genes＇　that　may　be　due　to　loss-of-function　mutations.　Together　these　two　types　of　mutations　drive　cancer　initiation　and　development.　Targeting　driver　gene　mutations　have　been　successfully　applied　to　the　treatment　of　various　cancers　in　humans.　In　this　review,　we　introduce　the　concept　of　driver　and　passenger　mutations,　and　theory　of　synthetic　lethality　(SL).　Furthermore,　we　address　the　application　of　SL　by　targeting　synthetic　lethal　partner　of　these　＇driver＇　genes　and　the　clinical　trial　that　can　be　designed　based　on　the　theory　of　SL.　Synthetic　lethal　interactions　arise　when　the　perturbation　of　more　than　one　genes　simultaneously　results　in　the　loss　of　viability,　whereas　a　deficiency　in　only　one　of　these　genes　does　not.　SL　might　be　extended　to　synthetic　sickness,　which　is　referred　to　the　sickness　but　not　lethality　in　cells　resulting　from　mutations　of　those　genes,　and　synthetic　dosage　lethality　by　targeting　its　partner　to　kill　cells　with　overexpression　of　one　gene.　This　theory　has　been　applied　to　genetic　studies　to　determine　functional　interactions　among　different　genes　for　decades　and　has　been　exploited　for　the　development　of　new　genotype-selective　anticancer　agents　in　engineered　human　tumor　cells.　In　precision　oncology,　the　theory　of　SL　provides　greater　promise　in　specifically　targeting　cancer　cells　with　genetic　mutations　but　not　in　normal　cells.　For　example,　targeting　both　of　the　breast-cancer　susceptibility　genes　1　and　2(BRCA1　and　BRCA2)　deficiencies　dramatically　sensitized　cells　to　poly(ADP-ribose)　polymerase　(PARP)　inhibitors　due　to　associated　defective　homologous　recombination,　which　leads　to　dysfunction　of　DNA　repair　in　cancer　cells.　Moreover,　oncogenic　drivers　such　as　RAS,　P53　are　not　＇druggable＇,　but　recently　these　oncogenic　drivers　have　been　studied　in　successfully　screening　for　their　synthetic　lethal　partners　or　agents.　If　a　synthetic　lethal　agent　can　be　combined　with　conventionally　chemotherapy,　this　will　probably　benefit　cancer　patients.　Therefore,　the　application　of　the　SL　in　cancer　researches　and　clinical　trials　might　represent　one　of　the　most　important　technological　breakthrough　in　the　treatment　of　cancer　in　the　era　of　precision　oncology.　©　2018,　Science　Press.　All　right　reserved.