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 members of the protein tyrosine phosphatase (PTP) class of enzymes that mediate signal transduction, and with certain MAP kinase kinases (MKK). In certain preferred embodiments siRNA modulate signal transduction pathways comprising SHP2, cdc14a/b, cdc25A/B/C, KAP, PTP-.epsilon., PRL-3, CD45, dual specificity phosphatase-3 (DSP-3), MKK-4, and/or MKK-7. Modulation of PTP-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. The invention also provides siRNA polynucleotides that interfere with expression of chemotherapeutic target polypeptides, such as DHFR, thymidylate synthetase, and topoisomerase I.