Abstract: Compositions and methods relating to small interfering RNA (siRNA) polynucleotides are provided as pertains to modulation of biological signal transduction. Shown are siRNA polynucleotides that interfere with expression of PTP1B, a member of the protein tyrosine phosphatase (PTP) class of enzymes that mediate signal transduction. In certain preferred embodiments siRNA modulate signal transduction pathways comprising human or murine PTP-1B and, in certain further embodiments, insulin receptor and/or Jak2. Modulation of PTP1B-mediated biological signal transduction has uses in diseases associated with defects in cell proliferation, cell differentiation and/or cell survival, such as metabolic disorders (including diabetes and obesity), cancer, autoimmune disease, infectious and inflammatory disorders and other conditions.