Solid organ transplantation, cytotoxic chemotherapy and hematopoietic stem cell transplantation are life-saving interventions for an increasing number of patients who now survive rather than succumb to their disease. These patients are left with compromised immunity, rendering them at risk for infection, often due to opportunistic and fastidious pathogens. The host inflammatory response to infection is attenuated in these scenarios, resulting in atypical (and often advanced) presentations of infection compared with immune-competent hosts. Traditional diagnostic approaches to infectious diseases rely on pathogen isolation in culture, which can be biased based on presence/absence of certain clinical features and result in delayed diagnosis and unnecessary exposure to broad spectrum antimicrobial therapy. Diagnostic platforms based on host gene expression profiles provide an innovative approach to the diagnosis of infectious diseases and can aid in rapid diagnosis to guide decisions regarding empiric and definitive therapy. Understanding how these platforms perform in immunocompromised patients – both for the diagnosis of infection and rejection – has the potential to revolutionize our approach to caring for transplant recipients and ultimately improve patient care.