Most rodent models of disease (in stroke research, anyway) use young, healthy male, inbred mouse strains kept under specific pathogen free (SPF) conditions, restricted antigen exposure in their environment, and on a diet optimized for maximum reproduction rates (high in antioxidants, trace elements and other supplements, etc.). It is like studying cohorts of 12 year old male identical twins kept on an identical health diet in a single sealed room, without any contact to the outside world (the ‘plastic bubble’). What may be good for reproducible modeling, is potentially problematic for translational research, as patients often have comorbidities (e.g. hypertension and diabetes in stroke), already take various medicines, are elderly, and include females… Thus, external validity of the models often is low, at least partially explaining some of the failures when moving from promising new therapeutic strategies in rodents to real life patients in randomized clinical trials. Fortunately, external validity can be improved by studying comorbid animals at advanced age and of both genders. It is trickier in rodents to produce a mature immune system that had contact with pathogens and multiple antigens. The answer to reduced genetic diversity may be to use populations specifically developed to provide wide genetic variability, such as the diversity outbred population or the partially inbred collaborative cross strains developed by the Jackson Laboratory. However, in my field (stroke research), which is particularly hit hard by the ‘translational roadblock’ I have not seen a single study making use of these strains.