INTRODUCTION: Advances in understanding the molecular mechanisms have led to the development of targeted therapies, which transformed the treatment of gastrointestinal stromal tumor (GIST). Sunitinib is an oral, multi-targeted tyrosine kinase inhibitor (TKI) that suppresses the activity of VEGFR, PDGFR, KIT; and plays a significant role in the second-line treatment of patients with GIST. AREAS COVERED: This article provides an overview of data on treatment of patients with advanced GIST, with particular focus on second-line therapy. It discusses the mechanisms of resistance, the findings of key clinical trials involving sunitinib and newer TKIs, and emerging therapeutic strategies (as velzatinib and ripretinib), including combination therapies (as bezuclastinib with sunitinib), immunotherapy and new molecules. The role of circulating tumor DNA (ctDNA) is also analyzed. EXPERT OPINION: Several drugs are currently available to enable sequential therapy in advanced disease; however, development of resistance associated with mutations in KIT and PDGFRA genes remains significant challenge. Ongoing research on new kinase inhibitors, use of ctDNA and combination therapies may in the future expand therapeutic options and enable more personalized treatment. The most probable new options that may replace sunitinib monotherapy in the second-line GIST treatment are combination of sunitinib with bezuclastinib, velzatinib, and molecularly profiled approach with ripretinib.