Gastric cancer is still the second leading cause of cancer death worldwide. Chemotherapy is one of the major treatment options for advanced gastric cancer. The efficacy of chemotherapy for gastric cancer is poor due to insensitivity and the development of multidrug resistance (MDR). Gastric cancer MDR involves a large number of molecules and complex mechanisms. Classical drug-resistant molecules, such as P-glycoprotein/ABCB1 and MRP1/ABCC1, have been found to play important roles in mediating MDR in some gastric cancers. In recent years, new molecules and mechanisms have been found to be associated with the development of gastric cancer MDR and might provide new targets for tackling gastric cancer MDR. Combined use of molecularly targeted therapy with chemotherapy may offer improved outcomes for gastric cancer patients and might provide new threads of hope for gastric cancer treatment.