Due to the advent of the screening programs for colorectal cancer and the era of quality assurance colonoscopy the number the polyps that can be considered difficult, including large (> 20 mm) laterally spreading tumors (LSTs), has increased in the last decade. All LSTs should be assessed carefully, looking for suspicious areas of submucosal invasion (SMI), such as nodules or depressed areas, describing the morphology according to the Paris classification, the pit pattern, and vascular pattern. The simplest, most appropriate and safest endoscopic treatment with curative intent should be selected. For LST-granular homogeneous type, piecemeal endoscopic mucosal resection should be the first option due to its biological low risk of SMI. LST-nongranular pseudodepressed type has an increased risk of SMI, and en bloc resection should be mandatory. Underwater endoscopic mucosal resection is useful in situations where submucosal injection alters the operative field, , for the resection of scar lesions, with no lifting, adjacent tattoo, incomplete resection attempts, lesions into a colonic diverticulum, in ileocecal valve and lesions with intra-appendicular involvement. Endoscopic full thickness resection is very useful for the treatment of difficult to resect lesions of less than 20 up to 25 mm. Among the indications, we highlight the treatment of polyps with suspected malignancy because the acquired tissue allows an exact histologic risk stratification to assign patients individually to the best treatment and avoid surgery for low-risk lesions. Endoscopic submucosal dissection is the only endoscopic procedure that allows completes en bloc resection regardless of the size of the lesion. It should therefore be indicated in the treatment of lesions with risk of SMI.