Wang, Cavanagh, and Green (1994) demonstrated a pop-out effect in searching for an unfamiliar target among familiar distractors (U-F search) and argued for the importance of a familiarity difference between the target and the distractors in determining search efficiency. In four experiments, we explored the generality of that finding. Experiment 1 compared search efficiency across a variety of target-distractor pairs. In Experiments 2, 3, and 4, we used Chinese characters and their transforms as targets and distractors and compared search performance between Chinese and non-Chinese participants. We demonstrated that search asymmetry and search efficiency in the U-F condition are influenced by the presence of low-level feature differences between the familiar and the unfamiliar stimuli. Our findings suggest that the familiarity of the distractors, rather than the familiarity difference between the target and the distractors, determines search efficiency. We also documented a counterintuitive familiarity-inferiority effect, suggesting that knowledge of search stimuli may, sometimes, be detrimental to search performance.