Human body is exposed to a large variety of chemical, biological and physical hazards, such as toxins, pathogens, pharmaceuticals, radiation and physical injury, just to name a few. These hazards induce damage to our organs and tissues and thereby adversely influence their function that is vital for human survival. Therefore, an episode of tissue injury is generally followed by a rapid and highly organized process of tissue repair and regeneration, and cells that are specialized to perform this duty are called somatic stem cells. These regenerative cells are highly dynamic in nature and respond to several internal and external stimuli, which includes genomic alterations, morphogens, inflammatory cytokines, growth factors, metabolites and microbial products, among others. We are using state-of-the-art genetics and single cell genomic technologies, as well as several in vivo and ex vivo 3D primary tissue culture models to understand how stem cells respond to these molecules in the presence or absence of injury. Findings from these studies are applicable in regeneration medicine.