Resonance Ionization Spectroscopy (RIS), an analytical technique with extremely high element specificity and sensitivity, is becoming recognized as an emerging field with wide applications. The sensitivity and selectivity of the RIS process is especially valuable for ultra-trace element analysis in semiconductor, geological, biological, and environmental samples, where the complexity of the matrix is frequently a serious source of interference. Using either Sputter-Initiated RIS (SIRIS) or Laser Atomization RIS (LARIS), it is possible to localize with high spatial resolution ultra-trace concentrations of a selected element to the sub-parts per billion level. The authors describe the implementation of RIS to solve a number of analysis problems and illustrate its salient characteristic with data from a wide range of applications. Results presented will include (a) concentration plots of ultra- trace elements in semiconductors and biological matrices, (b) characterization of dopants as a function of depth in semiconductors, (c) spatial distribution of natural uranium in bone and bone marrow, and (d) localization of stable isotope-labeled DNA in the development of faster DNA sequencing methods. The practical capabilities of SIRIS/LARIS to determine trace elements as a function of depth and lateral position in semiconductors and biological matrices are discussed.