In this paper, we describe recent studies for the geophysical and geomechanical characterization of soils in Hispaniola (Greater Antilles), an island threatened by the eventual rupture of major seismogenic fault systems. The investigations were performed for four different cities settled on complex geological formations in Haiti (Cap-Haïtien, Port-au-Prince) and the Dominican Republic (Santo Domingo, Santiago de los Caballeros). We present the complete methodology we implemented for mapping zones of homogeneous seismic response and for microzonation studies, but each main stage of investigation is described as it was conducted in one or two cities. Therefore, first we present our site-characterization technique applied to Santo Domingo and Santiago de los Caballeros, which is based on geotechnical data, geophysical multichannel analysis of surface waves, and ambient-noise recordings. Then we present the site-response analysis through numerical analysis with nonlinear soil models that we performed for the city of Cap-Haïtien. Finally, we describe the amplification factors for site-specific response spectra that we derived for the microzonation of Port-au-Prince. We argue for the implementation of a multidisciplinary approach built upon complementary field geological, geophysical, and geotechnical data rather than solely depending on geophysical measures for the characterization of VS30. In addition, we explore the compatibility of the soil classes recommended by the International Building Code (IBC) in the context of local seismic amplification.