sparkV10 is the next generation of the bioisostere software tool FieldStere. Building on FieldStere’s ability to find biologically equivalent replacements for key moieties in molecules, this update provides new capabilities including the XED3 force field, new clustering algorithms, and access to ADMET and physicochemical property predictions on bioisosteric replacements. Medicinal and computational chemists can use sparkV10 to generate novel active compounds by replacing sections of existing molecules with bioisosteric fragments. sparkV10 is available for deployment on standard desktop computers and can be integrated into workflow technologies.