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In this article, we discuss the optical immersion method based on refractive index matching of scatterers (e.g., collagen, elastin fibers, cells and cell compartments) and the ground material (interstitial fluid and/or cytoplasm) of tissue and blood under the action of exogenous optical clearing agents. We analyze the optical clearing of fibrous and cell-structured tissues and blood from the point of view of receiving more valuable, normally hidden, information from spectroscopic and polarization measurements, confocal microscopy, optical coherence and optical projection tomography, as well as from nonlinear spectroscopies, such as two-photon fluorescence and second-harmonic generation techniques. Some important applications of the immersion technique to glucose sensing, drug delivery monitoring, improvements of image contrast and imaging depth, nondistortive delivery of laser radiation and precision tissue laser photodisruption, among others, are also described.