GIST (gastrointestinal stromal tumors) represent 20% of sarcomatous tumors and 1–2% of primary gastrointestinal cancers. They have an excellent prognosis when localized and resectable, though their prognosis is poor in the metastatic setting, with limited options after the second line until recently. Four lines are now standard in KIT-mutated GIST and one in PDGFRA-mutated GIST. An exponential growth of new treatments is expected in this era of molecular diagnostic techniques and systematic sequencing. Currently, the main challenge remains the emergence of resistance linked to secondary mutations caused by selective pressure induced by TKIs. Repeating biopsies to tailor treatments might be a step in the right direction, and liquid biopsies at progression may offer a non-invasive alternative. New molecules with wider KIT inhibition are under investigation and could change the catalog and the sequence of existing treatments. Combination therapies may also be an approach to overcome current resistance mechanisms. Here, we review the current epidemiology and biology of GIST and discuss future management options, with an emphasis on genome-oriented therapies.