Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. The majority are sporadic, solitary tumors that harbor mutually exclusive KIT or PDGFRA gain-of-function mutations. The type of mutation in addition to risk stratification corresponds to the biological behavior of GIST and response to treatment. Up to 85% of pediatric GISTs and 10–15% of adult GISTs are devoid of these (KIT/PDGFRA) mutations and are referred to as wild-type GISTs (wt-GIST). It has been shown that these wt-GISTs are a heterogeneous tumor group with regard to their clinical behavior and molecular profile. Recent advances in molecular pathology helped to further sub-classify the so-called “wt-GISTs”. Based on their significant clinical and molecular heterogeneity, wt-GISTs are divided into a syndromic and a non-syndromic (sporadic) subgroup. Recently, the use of succinate dehydrogenase B (SDHB) by immunohistochemistry has been used to stratify GIST into an SDHB-retained and an SDHB-deficient group. In this review, we focus on GIST sub-classification based on clinicopathologic, and molecular findings and discuss the known and yet emerging prognostic and predictive genetic alterations. We also give insights into the limitations of targeted therapy and highlight the mechanisms of secondary resistance.