Sp1 is a transcription factor of the Sp/KLF family that binds to GC-rich motifs in regulatory regions of genes. Sp1 is involved in the regulation of cell proliferation, apoptosis and differentiation, and angiogenesis. A high level of SP1 expression, as well as its aberrant transcriptional activity due to post-translational modifications, is found in cells in oncological diseases, such as lung, breast, pancreatic, thyroid, gastric cancer, and glioma; congenital heart disease, as well as neurodegenerative disorders, including Huntington’s and Parkinson’s diseases. Binding of Sp1 to GC-rich motifs of the regulatory regions of the genes encoding components of the MAPK, p38, JAK/STAT, PI3K/Akt signaling pathways, is involved in the control of cell proliferation, differentiation, and death. In addition, kinases of these signaling pathways are able to change the transcriptional activity of Sp1 by phosphorylation of certain amino acid residues, which leads to a change in the efficiency of its binding to cofactors and DNA regulatory regions. This review presents data on the relationship between the Sp1 transcription factor and the activity of the MAPK, p38, JAK/STAT, and PI3K/Akt signaling pathways in normal tissues and in various pathologies, including malignant diseases.