Spider is a long-duration, balloon-borne polarimeter designed to measure large-scale cosmic microwave background (CMB) polarization with very high sensitivity and control of systematics. The instrument will map over half the sky with degree angular resolution in the I, Q, and U Stokes parameters in four frequency bands from 96 to 275 GHz. Spider's ultimate goal is to detect the primordial gravity-wave signal imprinted on the CMB B-mode polarization. One of the challenges in achieving this goal is the minimization of the contamination of B-modes by systematic effects. This paper explores a number of instrument systematics and observing strategies in order to optimize B-mode sensitivity. This is done by injecting realistic-amplitude, time-varying systematics into a set of simulated time streams. Tests of the impact of detector noise characteristics, pointing jitter, payload pendulations, polarization angle offsets, beam systematics, and receiver gain drifts are shown. Spider's default observing strategy is to spin continuously in azimuth, with polarization modulation achieved by either a rapidly spinning half-wave plate or a rapidly spinning gondola and a slowly stepped half-wave plate. Although the latter is more susceptible to systematics, the results shown here indicate that either mode of operation can be used by Spider.