Interleukin-33 (IL-33), a relatively new cytokine, has a higher binding affinity for ST2 receptor expressed by an array of immune cells including mast cells. Mast cells are essential for the development of anaphylaxis, allergy and asthma. Here, we examine the Yin and Yang functions elicited by IL-33 in umbilical cord blood derived mast cells (hCBMCs) using cellular, molecular and systems biological strategies. The CD34⁺ cells were isolated from human umbilical cord blood using Magnetic Activated Cell Sorting (MACS) method (Miltenyi Biotech, Germany) and differentiated into functional mast cells using AIM-V medium (ThermoFisher Scientific, USA) with rhIL-6 (50ng/mL) and rhSCF (100ng/mL) for 6 – 8 weeks. The purity of the mast cells was estimated using the flow cytometric examination of CD117 expression on the cell surface using FACS AriaIII (BD Biosciences, USA). The hCBMCs were stimulated using different concentrations of human IL-33 (10 – 20 ng/mL) and the RNA and proteins were isolated at different time points (0, 6h and 24h) for Affymetrix microarray analysis and multiplex cytokine analysis using human 30plex cytokine kit (LHC6003M) based on Luminex xMAP technology by MAGPIX machine (Luminex Corporation, USA). The raw microarray data was analyzed using Affymetrix Expression Console (ThermoFisher Scientific, USA) to obtain differentially expressed genes (DEGs) and further analyzed using Ingenuity Pathway Analysis (IPA) software (Qiagen, USA). The stimulation of hCBMCs by IL-33 leads to the activation of Th2 associated cytokine network, sphingosine kinase mediated signaling cascades, and subsequently triggered the production of various proinflammatory as well as anti-inflammatory cytokines, chemokines, cytokine receptors, and growth factors in a dose and time dependent manner.  The specific targeting of downstream proinflammatory signaling molecules initiated through IL-33/ST2 axis in mast cells might be considered for the management of anaphylaxis, allergy and asthma in a typical clinical setting.