A substantial amount of information is available concerning gastrointestinal colonization and invasion of the chicken gut by Gram-negative microorganisms such as Salmonella enterica and Campylobacter jejuni. Both bacterial and host factors of importance have been documented in relation to invasion of the chicken gastrointestinal tract. Both groups of microorganisms are associated with the gastrointestinal tract and have received major attention due to the zoonotic aspect of these infections. In contrast, other important poultry pathogens without this potential have been poorly characterized concerning sites of infection and pathogenesis. After the ban on antibiotic growth promoters an increasing number of infections due to Enterococcus and Streptococcus spp. have been observed in poultry in Denmark. This chapter describes the invasive potential of these organisms in the chicken gut compared to the same ability among different serotypes of Salmonella enterica. In addition, the invasive potential of Pasteurella multocida is described. The methods used included an in vivo intestinal loop model in chickens and several cell culture lines. Surprisingly, some of our most recent investigations have demonstrated significant differences in the invasive properties in the gut of Enterococcus hirae and different Streptococcus species using both the loop model and avian macrophage and intestinal epithelial cell cultures. The Gram-positive cocci have mainly been associated with septicaemic conditions in young chickens, endocarditis and septicaemia in adult birds, and also with amyloid arthropatia during rearing. Similar disease conditions in humans-in particular, endocarditis-may be observed. The significance of these findings, including comparative aspects, will be discussed.