Only a minority of the oral microbial community can adhere to hard and soft oral tissues, and assembly of the complex oral biofilm is accomplished by subsequent adherence of secondary colonizers. Streptococcus is an early colonizer and Fusobacterium has a propensity for co-aggregation with many genera, forming a bridge between early and late colonizers in the oral biofilm. Thus, on the one hand, the observed decrease in prevalence of Streptococcus and increased abundance of Fusobacterium genera in pre-cancers could reflect the altered surface properties of the cancer cells and stroma, which might no longer support adhesion of streptococci. On the other hand, we can hypothesize that shifts in abundance of these two genera could result in an enhanced pro-inflammatory environment, since Streptococcus species have been reported to attenuate Fusobacterium nucleatum induced pro-inflammatory responses of oral epithelial cells. We also note that Fusobacterium nucleatum grown as a biofilm is capable of invading organotypic cultures, and secondly, that the organism has recently been reported in colon cancers, further supporting a potential role in oral cancer. The oral cavity offers a relatively unique opportunity to screen at risk individuals for cancer, because the lesions can be seen, and as we report here, the shift in the microbiome of the cancer and pre-cancer lesions compared to anatomically matched clinically normal tissue from the same individual can be detected in non-invasively collected swab samples. Saliva is another noninvasively collected oral sample composed largely of bacterial cells, but also shed epithelial and immune cells. A variety of “omics” biomarkers in saliva have been proposed for use in diagnosis of oral cancer, including metabolites, proteins, transcribed genes, miRNAs, genome alterations and epigenomic changes, as well as the microbiome. For the microbiome, however, saliva may not be optimal. Saliva bathes the entire oral cavity, resulting in a loss of information on the subsite specific composition of bacterial communities. Moreover, with saliva, there is no possibility to use each individual as his or her own control, and so account for the substantial variation in the oral microbiome amongst individuals. Non-invasively sampling the microbiome of oral lesions and corresponding normal tissue opens the possibility to not only detect cancer-associated changes at one time point, but the relative stability of the adult oral microbiome also offers the opportunity to monitor shifts in bacterial communities over time. Here we observed changes in the microbiome, which, in future larger studies, may be confirmed as a potential biomarker of oral cancers or pre-cancers, and may even have utility to discriminate patients with lymph node metastases. In addition, there are other challenges in clinical management of oral cancers and pre-cancers that would benefit from better diagnostic tools.