Many strategies for biosignature detection rely on the identification of well-established and widely accepted features associated with terrestrial life and signatures of biologic processes, such as particular classes of molecules and isotopic signatures, enantiomeric excesses, and patterns within the molecular weights of fatty acids or other lipids. Yet life may be vastly different on other worlds, such as the icy moons of Jupiter and Saturn. This talk will discuss “agnostic” approaches to in situ life detection—methods that might enable us to identify unknowable, unfamiliar features and chemistries—by utilizing existing instrumentation in more inclusive ways, pursuing new leads, and synthesizing data with probabilistic approaches.