Since the first reports of a novel severe acute respiratory syndrome (SARS)-like coronavirus in December 2019 in Wuhan, China, there has been intense interest in understanding how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in the human population. Recent debate has coalesced around two competing ideas: a ‘‘laboratory escape’’ scenario and zoonotic emergence. Here, we critically review the current scientific evidence that may help clarify the origin of SARS-CoV-2. EVIDENCE SUPPORTING A ZOONOTIC ORIGIN OF SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 Coronaviruses have long been known to present a high pandemic risk. Severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) is the ninth documented coronavirus that infects humans and the seventh identified in the last 20 years (Lednicky et al., 2021; Vlasova et al., 2021). All previous human coronaviruses have zoonotic origins, as have the vast majority of human viruses. The emergence of SARS-CoV-2 bears several signatures of these prior zoonotic events. It displays clear similarities to SARS-CoV that spilled over into humans in Foshan, Guangdong province, China in November 2002, and again in Guangzhou, Guangdong province in 2003 (Xu et al., 2004). Both these SARS-CoV emergence events were associated with markets selling live animals and involved species, particularly civets and raccoon dogs (Guan et al., 2003), that were also sold live in Wuhan markets in 2019 (Xiao et al., 2021) and are known to be susceptible to SARS-CoV-2 infection (Freuling et al., 2020). Animal traders working in 2003, without a SARS diagnosis, were documented to have high levels of immunoglobulin G (IgG) to SARSCoV (13% overall and >50% for traders specializing in civets) (Centers for Disease Control and Prevention, 2003). Subsequent serological surveys found 3% positivity rates to SARS-related coronaviruses (SARSr-CoV) in residents of Yunnan province ll OPEN ACCESS 4848 Cell 184, September 16, 2021 ª 2021 The Author(s). living close to bat caves (Wang et al., 2018), demonstrating regular exposure in rural locations. The closest known relatives to both SARS-CoV and SARS-CoV-2 are viruses from bats in Yunnan, although animals from this province have been preferentially sampled. For both SARS-CoV and SARS-CoV-2, there is a considerable geographic gap between Yunnan and the location of the first human cases, highlighting the difficulty in identifying the exact pathway of virus emergence and the importance of sampling beyond Yunnan. SARS-CoV-2 also shows similarities to the four endemic human coronaviruses: human coronavirus-OC43 (HCoV-OC43), human coronavirus-HKU1 (HCoV-HKU1), human coronavirus229E (HCoV-229E), and human coronavirus NL63 (HCoVNL63). These viruses have zoonotic origins, and the circumstances of their emergence are unclear. In direct parallel to Figure 1. Phylogenetic and epidemiological data on the early COVID-19 pandemic in Wuhan (A) Phylogenetic tree of early SARS-CoV-2 genomes sampled from Wuhan during December 2019–January 2020. The split between lineages A and B is labeled with the coordinates and base of the two differentiating nucleotide mutations. Cases with a known association to the Huanan or other markets are denoted by symbols (reported in World Health Organization, 2021). (B) Map of districts of Wuhan showing the location of markets, the Wuhan National Biosafety Laboratory at the Zhengdian Scientific Park of the Wuhan Institute of Virology (denoted WIV), where the coronavirus isolation and culture work of Dr. Shi Zhengli is performed, and the earliest known cases. (C–E) Location of recorded COVID-19 cases in Wuhan from December 8 to December 31, 2019. Cases with a home address outside of Wuhan city are not shown. (F–H) Map of districts of Wuhan indicating the first record of excess deaths due to pneumonia (shaded green) from January 15, 2020. Case and excess death data were extracted and redrawn from figures provided in World Health Organization (2021). See also Document S1. SARS-CoV-2, HCoV-HKU1, which was first described in a large Chinese city (Shenzhen, Guangdong) in the winter of 2004, has an unknown animal origin, contains a furin cleavage site in its spike protein and was originally identified in a case of human pneumonia (Woo et al., 2005). Based on epidemiological data, the Huanan market in Wuhan was an early and major epicenter of SARS-CoV-2 infection. Two of the three earliest documented coronavirus disease 2019 (COVID-19) cases were directly linked to this market selling wild animals, as were 28% of all cases reported in December 2019 (World Health Organization, 2021). Overall, 55% of cases during December 2019 had an exposure to either the Huanan or other markets in Wuhan, with these cases more prevalent in the first half of that month (World