Injurious challenges, including infection by pathogenic microbes, exposure to toxins or toxic agents, and trauma, frequently cause massive tissue damage as well as organ functional abnormality or dysfunction. Mediators derived from invading pathogens and injured host tissues, specifically pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) can be recognized by various types of pattern recognition receptors (PRRs) expressed by host cells to trigger the host defense response. Ligand engagement of these PRRs, including Toll-like receptors (TLRs), NOD-like receptors (NLRs), C-type lectin receptors (CLRs), retinoic acid-inducible gene-I-like receptors (RLRs), and absent in melanoma 2-like receptors (ALRs) among others on cell surface and in intracellular compartments, turns on their associated signaling pathways to activate immune cells as well as parenchymal and nonparenchymal cell types in vital organ systems. Upon activation, cells adjust their metabolic and functional activities as well as dynamically produce both pro- and anti-inflammatory mediators, including cytokines, chemokines, growth factors, vasoactive substances, proteases and their inhibitors, and eicosanoids, to mediate the host response for eliminating invading pathogens, resisting injury, clearing devitalized cell tissue debris, repairing damaged tissue, and eventually restoring the integrity of organ tissue function. Recent investigations have revealed that during processes of the host defense response, tissue Injury and repair, cell conversion of phenotype and change in fate, specifically acquisition of upstream precursor features, is a unique phenomenon. This conversion of cells commonly accompanies transcriptional alteration/adjustment for enhancing cell proliferation and commitment to differentiation toward cell types urgently required for defending against injury, repairing structural damage, and restoring the integrity of organ tissue function. The extent of cell conversion varies dependent on types of cells as well as characteristics of injuries. The accompanied fate change in cells can be in forms from state transition (such as transient alteration or in plastic state) to comprehensive reprogramming (i.e. stable fate switch). Further, different cell types can exhibit distinctive arrays in signaling regulation and functional alteration. Better understanding of the underlying mechanisms is critical for advancing regenerative medicine and developing novel therapeutic strategies to promote host defense as well as optimal repair of organ tissue injury. This article reviews recent progress in investigation on conversion of cells in different tissue environments during the host defense response, tissue injury and repair with focus on bone marrow, vascular endothelium, lung, liver, and intestine. The mechanisms of signaling regulation for cell conversion and fate change are discussed. Efforts in exploring the correlated therapeutic approaches are also addressed.