Replace 意為「取代，代替；更換，替換」，而 substitute 意為「取代；代替」，但這兩者並非同義詞，因為它們的用法並不相同。replace 僅當及物動詞用，而 substitute 則可當及物和不及物動詞，如 He’ll have to replace those tires; they’re badly worn. (他必須更換那些輪胎；它們磨損得太厲害了)；George has replaced John as captain of the team. (喬治接替約翰當了隊長)；Susan is ill and Laura is to substitute her. (蘇珊病了，羅拉將代替她)；George has substituted as captain of the team. (喬治代任隊長)。
這兩個動詞最大的差異在於其後所接的介系詞，replace 後面可接 with 或 by (尤其是在被動態中)，而 substitute 都是接 for，如 We’ve replaced old calculators with/by computers. (我們已用電腦取代了舊式的計算機)；Her photograph was replaced by his painting. (她的照片被他的畫取代了)；Home-made parts are being substituted for imported ones. (國產零件取代進口零件)。
必須注意的是，許多人搞不清楚這兩個字在上下文中的替代關係：to replace A with/by B 意為「用 B 來替換 A」，亦即 A 被 B 所取代，而 to substitute A for B (or A be substituted for B) 意為「用 A 來替換 B」，亦即 B 被 A 所取代。例如：
I replaced her photograph with/by his painting. (我用他的畫代替她的照片)。
= I substituted his painting for her photograph.
= Her photograph was replaced by his painting.
= His painting replaced her photograph.
= His painting was substituted for her photograph.
儘管目前 substitute 被用來代替 replace 的情況有越來越多的趨勢，但謹慎的人士仍堅守並維持它們之間的不同。