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The limited prognostic value of currently used histologic classifications of gastric cancer and their failure to account for the complexity of the disease as revealed by more recent investigations prompted a combined reinvestigation of histologic, molecular, and clinicopathologic patterns in 294 extensively sampled, invasive gastric cancers representing all main histotypes and stages of the disease and followed for a median of 150 months. Among histologic parameters tested, only cellular atypia, angio-lympho- or neuroinvasion, Ki67 proliferation index, expansile/infiltrative type growth, and T8 cell-rich high lymphoid intra-/peritumor response (HLR) proved to be stage-independent predictors of patient survival. Among molecular tests, p53 gene exon 7 (loop 3) and 8 (loop-sheet-helix motif and S-10 band), but not p53 protein overexpression, TP53 LOH or 18qLOH, were found to worsen prognosis. Microsatellite DNA instability was a favorable prognostic factor when coupled with HLR. Patient survival analysis of the main histotypes and their subtypes confirmed the favorable prognosis of HLR, well-differentiated tubular, muconodular, and low grade diffuse desmoplastic cancers, and highlighted the worse prognosis of anaplastic and infiltrative-lymphoinvasive mucinous cancers compared to ordinary cohesive and diffuse cancers. Distinct roles of individual morphologic and molecular factors in tumor progression of the different histotypes have been recognized. The combination of survival-predictive histotypes and individual histologic or molecular parameters allowed us to develop a classification of all gastric cancers into three grades of increasing malignancy which proved to be of high prognostic value.