Two distinct mitogenic modes coexist in thyroid epithelial cells. TSH via cAMP induces proliferation and differentiation expression, whereas growth factors including epidermal growth factor (EGF) induce proliferation and dedifferentiation. Divergent models of TSH/cAMP-dependent mitogenesis have emerged from different thyroid cell culture systems. In the FRTL-5 rat cell line, cAMP cross-signals with transduction pathways of growth factors to induce cyclin D1 and p21(cip1) and down-regulate p27(kip1). By contrast, in canine primary cultures, mitogenic pathways of cAMP and growth factors are fully distinct. cAMP does not induce D-type cyclins and p21, it up-regulates p27, and it stimulates the formation and activity of cyclin D3-cyclin-dependent kinase (CDK) 4 complexes. In primary cultures of normal human thyrocytes, EGF + serum increased cyclin D1 and p21 accumulation, and it stimulated the assembly and activity of cyclin D1-CDK4-p21 complexes. By contrast, TSH repressed or did not induce cyclin D1 and p21, and it rather up-regulated p27. TSH did not increase cyclin D1-CDK4 activity, but it stimulated the activating phosphorylation of CDK4 and the pRb-kinase activity of preexisting cyclin D3-CDK4 complexes. As recently demonstrated in dog thyrocytes and other systems, cyclin D1 and cyclin D3 differently oriented the site specificity of CDK4 pRb-kinase activity, which might differently impact some pRb functions. Cyclin D1 or cyclin D3 are thus differentially used in the distinct mitogenic stimulations by growth factors or TSH, and potentially in hyperproliferative diseases generated by the overactivation of their respective signaling pathways. At variance with dog thyroid primary cultures, rat thyroid cell lines might not be valid models of TSH-dependent mitogenesis of human thyrocytes.