Vibrio cholerae, a Gram-negative bacterium is known as the causative agent of cholera, acute watery diarrhoea. Out of approximately 206 serogroups of V. cholerae, only O1 and O139 are thought to be capable of causing epidemic cholera. These serogroups contain genes for cholera toxin (CT) and toxin-coregulated pilus (TCP). Strains belonging to about 204 other than O1 and O139 serogroups are collectively referred to as non-O1, non-O139 strains. The majority of non-O1, non-O139 strains do not contain genes for CT and/or TCP, although the gene for toxin regulatory protein (ToxR) is genaerally present in these strains. These strains are ubiquitous in aquatic environments and have been recognized as the causative agents of sporadic cholera-like disease and outbreaks. Over the passed two decades, a sharp increase in the number of non-O1, non-O139 infections worldwide has been observed. Furthermore, non-O1, non- O139 V. cholerae is also associated with extra-intestinal infections such as inguinal skin, soft tissue, ear, wound, and primary pulmonary infections, bacteraemia causing hypotensive shock, leukopenia, decreased platelet counts, severe hypoalbuminemia, peritonitis and septicaemia. Although V. cholerae O10, O12, O31, O37, O53, and O141 serogroups are reported to be associated with cholera-like epidemics, it is yet to be established whether a definite sets of serotypes of non-O1, non-O139 are intrinsically more pathogenic than others. Furthermore, the pathogenic mechanisms by which these enteropathogens cause diarrhoea are not yet well established and the pathogenesis of invasive non-O1, non-O139 V. cholerae infections is not yet well understood. Recently, several evidences of occurrences of the toxin-coregulated pilus (TCP) pathogenicity island encoding TCPs, and the CTX prophage encoding cholera toxin, TCP island alone making the non-O1 strains susceptible to transduction with CTX phage, Vibrio seventh pandemic islands (VSP-1 and VSP-2), type III secretion system (TTSS) genes, and putative accessory virulence genes (mshA, hlyA, and rtx) among the non-O1, non-O139 isolates have been documented. Since some of the pathogenic strains of V. cholerae O1 and O-139 retain these genes, they might play an important role in the emergence of newer V. choleare pathogens most likely depending on assembling a grouping of genes for both ecological suitability and virulence to attain epidemiological prevalence. In addition, a high proportion of reported V. cholerae non-O1, non-O139 isolates from clinical and/environmental sources are multiple antibiotic resistant. Thus it has become increasingly clear that the non-O1, non-O139 serogroups are involved in the emergence of newer variant of V. cholerae. The present review will focus on the current perspectives on the disease spectrum, ecology and environmental studies, virulence factors and pathogenicity, biochemical characteristics, diagnosis and treatment of non-O1, non-O139, to clarify the public health significance and epidemiological potential of V. cholerae non- 1, non-O139 infections. © 2011 by Nova Science Publishers, Inc. All rights reserved.