Background: We hypothesized that NGS could identify genomic alterations that guide selection of targeted therapies and discover novel drug targets for primary and metastatic CRC. Methods: DNA was extracted and sequenced from 4 X 10 μ FFPE sections from 40 (32 primary and 8 metastatic) CRCs obtained from 2004-10 (52% male; 48% female; mean age 60 years; 10% Stages I/II; 40% Stage III; 40% Stage IV; 10% Stage unknown) using a targeted NGS assay in a CLIA laboratory (Foundation Medicine). 2574 exons of 145 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer were fully sequenced for point mutations, insertions/deletions, copy number alterations (CNAs) and select gene fusions. Results: NGS revealed 125 genomic alterations in 39/40 tumors (mean 3.1, range1-7) in 21 genes, including 80 base substitutions (64%), 39 insertions/deletions (31%), 4 CNAs (3%) and 2 gene fusions (1.6%). TP53 and APC were altered in 80% (32/40) and 67.5% (27/40) of CRCs respectively, with both mutated more frequently than reported in COSMIC. Alterations associated with potential sensitivity to targeted therapies were identified in 21 (52.5%) of CRCs including: 10 KRAS (TK/MEK inhibitors), 6 BRAF (BRAF inhibitors), 5 FBXW7 (mTOR inhibitors); 2 PIK3CA (PI3K/mTOR inhibitors); 2 BRCA2 (PARP inhibitors); 2 GNAS (MEK/ERK inhibitors) and 1 CDK8 (CDK inhibitors). In 1 CRC, a 5.2 Mb tandem duplication generated a novel C2orf44-ALK gene fusion starting at the canonical exon 20 recombination site previously reported for the majority of ALK gene fusions. cDNA sequencing identified an 90-fold increase in 3’ ALK expression, suggesting the C2orf44-ALK fusion results in ALK kinase domain overexpression and contains the same intracellular domain as other ALK fusions including the ALK inhibitor sensitive EML4-ALK. Conclusions: NGS of broad, cancer-related gene content from FFPE CRC samples uncovered an unexpectedly high frequency of genomic alterations, many of which may be clinically actionable by informing treatment decisions, including a novel ALK gene fusion. This previously unrecognized subset of CRC patients may be candidates for clinical trials of crizotinib or other ALK inhibitors.