Foot-and-mouth disease (FMD) in adult sheep usually causes milder clinical signs than in cattle or pigs, and is often subtle enough to go undiagnosed. In contrast, FMD in lambs has been reported to cause high mortality during field outbreaks. In order to investigate the pathogenesis of FMD in lambs, two groups, aged 10-14 days, were infected with foot-and-mouth disease virus (FMDV) type O UKG. One group of lambs (n=8) was inoculated with FMDV in the coronary band, while the other (n=4) was infected by direct contact with FMDV-inoculated ewes. Daily serum samples and temperature measurements were taken. Lambs were killed sequentially and tissue samples taken for analysis. Using real-time RT-PCR, viral RNA levels in tissue samples and serum were measured, and a novel strand-specific real-time RT-PCR assay was used to quantify viral replication levels in tissues. Tissue sections were examined for histopathological lesions, and in situ hybridisation (ISH) was used to localise viral RNA within histological sections. The contact-infected lambs became infected approximately 24h after the ewes were inoculated. Vesicular lesions developed on the feet of all lambs and on the caudo-lateral part of the tongues of six of the eight inoculated lambs and three of the four contact-infected lambs. Although no lambs developed severe clinical signs, one of the contact-infected lambs died acutely at 5 days post-exposure. Histological examination of the heart from this lamb showed multi-focal areas of lymphocytic-plasmacytic myocarditis; similar lesions were also observed in the hearts of three of the inoculated lambs. Using ISH, viral RNA was localised within cardiac and skeletal muscle cells from the lamb which had died, and also from vesicular lesions on the coronary band and tongue of inoculated lambs. These results provide a detailed description of the pathogenesis of the disease in lambs.