Colorectal cancer (CRC) is the most common type of malignant tumor in the digestive tract. Rectal cancer (RC), which accounts for approximately half of CRC, occurs mainly in people aged >45 years, with a higher incidence in men than in women. 1,2In the USA, in 2020, it was estimated that 104,610 cases of colon cancer and 43,340 cases of RC would be diagnosed, and a total of 53,200 patients would die from these cancers (Siegel et al., 2020). In China, in 2015, the number of cases of colorectal cancer was 376,300 and colorectal cancer-related deaths were 191,000 (Schmoll et al., 2018). Locally advanced rectal cancer (LARC) accounts for a considerable proportion of patients, which is defined by the presence of a T3/T4 cancer, with or without lymph node infiltration (N0/N+) and no metastatic dissemination (Glynne-Jones et al., 2017). However, there is lack of international consensus on the definition of LARC. These definitions are divided into tumor growth to the mesentery, presence of 1 mm or less rectal mesenteric fascia, invasion of adjacent organs or structures (T4), and lymph node metastasis. The common factor in these definitions is the high risk of not being able to cure the disease locally (Zwart et al., 2022). Surgeries have long been the main treatment for LARC; however, historically, the effect of surgery alone has been unsatisfactory, with a local recurrence (LR) rate as high as 50% (Devitt, 2002). The emergence of total mesorectal excision (TME) and a series of research of perioperative radiotherapy (RT) have allowed the LR rate to be better controlled. Today, neoadjuvant chemoradiotherapy (nCRT) is the standard treatment for LARC in most countries, and short-course RT in a few countries, due to their benefits in reducing the LR (Sauer et al., 2004). Although, there are still some unmet needs, the pathologic complete response (pCR) rate is unsatisfactory and distant metastasis is the leading cause of cancer death (De Felice et al., 2016, Ceelen et al., 2009). Moreover, although adjuvant chemotherapy has been recommended in patients with LARC, clear benefit of this therapy in improving overall survival (OS) has not been proven, which may be related to poor patient compliance. A series of research has been done to address the issues; this review aims to provide an overview of various neoadjuvant strategies in the treatment of LARC, including adding agents to nCRT, prolonging the interval between RT and surgery, and delivery of chemotherapy in the neoadjuvant setting. Considering the impact of the toxicity of chemoradiotherapy (CRT) on the quality of life of patients, this review will also explore the value of immunotherapy and selective removal of RT. Genomic or radiomic determinants of response to neoadjuvant therapy are also discussed.