We live in an era of personalized medicine and the knowledge about pathophysiology of diffuse gastric cancer has had many advances. Thus, the role of this work is to clarify what is new from diagnosis to treatment of this disease in order to treat patients in the most tailored manner as possible.  Almost all phase III trials in gastric cancer have been performed without taking in consideration histologic subtypes, i.e. they have disregarded the differences between diffuse gastric cancer and general gastric cancer. However, the clinical practice reveals that diffuse gastric cancer is a completely distinct disease, with an aggressive course and generally worse prognosis. The loss of cohesion between tumor cells due to the loss of E-cadherin synthesis is the critical point on the oncogenesis of diffuse gastric cancer and is at the root of its marked heredity.