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A discussion of return of genetic research results requires a common understanding of how final results are generated and what the scope of potential results may be. To this end, we provide a brief overview of the steps by which human genomic data, whether in the clinical or research setting, are generated and interpreted. We cover (1) DNA targeting methods, (2) sequencing, (3) mapping, (4) variant calling, (5) annotation, and (6) interpretation. As powerful as this technology is, we point out technical, scientific, and clinical limitations that inject uncertainty into interpretations based on genotypic data alone. Given these considerations, we then discuss ethical issues that arise as decisions are made regarding how human genomic data are generated and interpreted in the research setting, and we propose an ethical framework by which researchers can assert policies at the points of control that maximize rewards, while minimizing risks.