Genomic sequencing technology is moving rapidly from the research setting into clinical medicine but significant technological and interpretive challenges remain. Exome sequencing (ES) in its recent clinical application provides a genetic diagnosis in about 25 per cent of cases (Berg 2014). While this diagnostic yield is substantial, it also indicates that in a majority of cases, patients are receiving negative results (i.e. no explanatory genetic variant found) from this technology. There are a number of uncertainties regarding the meaning of a negative result in the current context of ES. A negative result may be due to current technological limitations that hinder detection of disease‐causing variants or to gaps in the knowledge base that prohibit accurate interpretation of their pathogenicity; or it may indicate that there is not a genetic etiology for the disorder. In this paper we examine the uncertainties and nuances of the negative result from genome sequencing and how both clinicians and patients make meaning of it as revealed in ethnographic observations of the clinic session where results are returned, and in interviews with patients. We find that clinicians and patients construct the meaning of a negative result in ways that are uncertain, contingent, and multivalent; but invested with optimism, promise, and potentiality.