Colorectal cancer (CRC) is the third most common cancer worldwide and is perhaps the best understood of all cancers. Although rapid advances have been made in patient management and therapy for most forms of CRC, our understanding of sporadic early-onset rectal cancer (RC) is limited which interestingly forms the predominant subtype among Indian CRC patients. More importantly, rectal tumors are known to be associated with a rapid metastatic spread and poor survival. We have performed the first comprehensive molecular characterization of rectal tumor samples from India. Surprisingly, a significantly high proportion of early-onset rectal tumors (as against late-onset) do not harbor either of the two canonical tumorigenesis pathways namely Wnt signaling and mismatch repair defect that drive a majority of colorectal tumors; the age specific difference is not significant in colon tumors. Interestingly however, the Wnt- early-onset rectal tumors exhibit extensive chromosomal instability, as determined through microarray-based comparative genomic hybridization. In addition, KRAS mutation is significantly low in early as against late-onset rectal tumors; there is no difference however with respect to p53 status. Efforts are currently underway, using next generation RNA sequencing and genome-wide transcript profiling through microarrays, to understand the biology of this unique CRC subtype. In parallel, our comprehensive studies on the familial cancer syndrome Hereditary Non-Polyposis Colorectal Cancer has revealed involvement of novel genes among Indian patients.