In order to realize the benefits of personalized cancer therapy, increasing demands are placed upon clinical laboratories to provide timely, comprehensive, clinically actionable, and analytically valid information regarding the genomic profile of individual patients’ tumor specimens. We have employed both next generation sequencing (NGS) technologies as well as DNA microarrays to comprehensively profile solid tumors for diagnostic, prognostic, and therapeutic indications. We have developed a custom NGS-based panel test to interrogate all exons for 397 genes, as well as most introns for a subset of 28 genes. The NGS panel detects several types of genomic alterations, including coding missense, nonsense, splice variants, insertions/deletions, focal gene amplifications, homozygous deletions, and selected rearrangements. Reportable variants are classified as either clinically significant with in-depth annotation regarding clinical relevance, relevant therapies and clinical trials, or variants of uncertain clinical significance with limited annotation. The DNA microarray complements the NGS assay by assessing genome-wide chromosome structural changes including gains, losses, focal gene amplifications, and copy-neutral events such as loss of heterozygosity (LOH). Direct involvement of clinical lab directors, pathologists, oncologists, and radiologists in our institution’s working tumor conferences via the presentation of in-house laboratory findings enhances both patient care and the educational environment via better informed discussion of unique patient specific findings.