Central to spintronics is the interconversion between electronic charge and spin currents, and this can arise from the chirality-induced spin selectivity (CISS) effect. CISS is often studied as magnetoresistance (MR) in two-terminal (2T) electronic nanodevices containing a chiral (molecular) component and a ferromagnet. However, fundamental understanding of when and how this MR can occur is lacking. Here, we uncover an elementary mechanism that generates such an MR for nonlinear response. It requires energy-dependent transport and energy relaxation within the device. The sign of the MR depends on chirality, charge carrier type, and bias direction. Additionally, we reveal how CISS can be detected in the linear response regime in magnet-free 2T nanodevices, either by forming a chirality-based spin-valve using two or more chiral components or by Hanle spin precession in devices with a single chiral component. Our results provide operation principles and design guidelines for chirality-based spintronic nanodevices and technologies.