Pancreatic　cancer　(PC)　is　assumed　to　be　an　intimidating　and　deadly　malignancy　due　to　being　the　leading　cause　of　cancer-led　mortality,　predominantly　affecting　males　of　older　age.　The　overall　(5　years)　survival　rate　of　PC　is　less　than　9%　and　is　anticipated　to　be　aggravated　in　the　future　due　to　the　lack　of　molecular　acquaintance　and　diagnostic　tools　for　its　early　detection.　Multiple　factors　are　involved　in　the　course　of　PC　development,　including　genetics,　cigarette　smoking,　alcohol,　family　history,　and　aberrant　epigenetic　signatures　of　the　epigenome.　In　this　review,　we　will　mainly　focus　on　the　genetic　mutations　and　epigenetic　signature　of　PC.　Multiple　tumor　suppressor　and　oncogene　mutations　are　involved　in　PC　initiation,　including　K-RAS,　p53,　CDKN2A,　and　SMAD4.　The　mutational　frequency　of　these　genes　ranges　from　50　to　98%　in　PC.　The　nature　of　mutation　diagnosis　is　mostly　homozygous　deletion,　point　mutation,　and　aberrant　methylation.　In　addition　to　genetic　modification,　epigenetic　alterations　particularly　aberrant　hypermethylation　and　hypomethylation　also　predispose　patients　to　PC.　Hypermethylation　is　mostly　involved　in　the　downregulation　of　tumor　suppressor　genes　and　leads　to　PC,　while　multiple　genes　also　represent　a　hypomethylation　status　in　PC.　Several　renewable　drugs　and　detection　tools　have　been　developed　to　cope　with　this　aggressive　malady,　but　all　are　futile,　and　surgical　resection　remains　the　only　choice　for　prolonged　survival　if　diagnosed　before　metastasis.　However,　the　available　therapeutic　development　is　insufficient　to　cure　PC.　Therefore,　novel　approaches　are　a　prerequisite　to　elucidating　the　genetic　and　epigenetic　mechanisms　underlying　PC　progression　for　healthier　lifelong　survival.