In recent years, organ preservation has been considered a feasible alternative to total mesorectal excision for patients with locally advanced rectal cancer with a clinical complete response to neoadjuvant therapy. However, the degree of tumor response to neoadjuvant therapy is variable. A fraction of the patients who did not achieve a complete response had grossly visible tumors. These patients, with clearly incomplete clinical response, need a total mesorectal excision. In addition, some patients with a significant tumor response still have some abnormalities in the bowel wall, such as superficial ulceration or tissue nodularity, which, while not conclusive for the presence of a tumor, are indicative of the possibility of a residual tumor in the bowel wall or in mesorectal lymph nodes. The management of patients with a so-called near-complete clinical response to neoadjuvant therapy is controversial. In this article, we will review the clinical and radiological criteria that define a clinical response to neoadjuvant therapy, possible treatment strategies, and follow-up protocols. We will also discuss patient and tumor characteristics that in our opinion can be useful in selecting the most appropriate treatment alternative. Although organ preservation and quality of life are important, the primary goal of treatment for these patients should be local tumor control and long-term survival.