The response to neoadjuvant chemoradiation therapy is an important prognostic factor for locally advanced rectal cancer. Although the majority of the patients after neoadjuvant therapy are referred to following surgery, the clinical data show that complete clinical or pathological response is found in a significant proportion of the patients. Diagnostic accuracy of confirming the complete response has a crucial role in further management of a rectal cancer patient. As the rate of clinical complete response, unfortunately, is not always consistent with pathological complete response, accurate diagnostic parameters and predictive markers of tumor response may help to guide more personalized treatment strategies and identify potential candidates for nonoperative management more safely. The management of complete response demands interdisciplinary collaboration including oncologists, radiotherapists, radiologists, pathologists, endoscopists and surgeons, because the absence of a multidisciplinary approach may compromise the oncological outcome. Prediction and improvement of rectal cancer response to neoadjuvant therapy is still an active and challenging field of further research. This literature review is summarizing the main, currently known clinical information about the complete response that could be useful in case if encountering such condition in rectal cancer patients after neoadjuvant chemoradiation therapy, using as a source PubMed publications from 2010–2021 matching the search terms “rectal cancer”, “neoadjuvant therapy” and “response”.