As strings are immutable in Python, just create a new string which includes the value at the desired index.

Assuming you have a string s, perhaps s = "mystring"

You can quickly (and obviously) replace a portion at a desired index by placing it between "slices" of the original.

s = s[:index] + newstring + s[index + 1:]

You can find the middle by dividing your string length by 2 len(s)/2

If you're getting mystery inputs, you should take care to handle indices outside the expected range

def replacer(s, newstring, index, nofail=False):
    # raise an error if index is outside of the string
    if not nofail and index not in range(len(s)):
        raise ValueError("index outside given string")

    # if not erroring, but the index is still not in the correct range..
    if index < 0:  # add it to the beginning
        return newstring + s
    if index > len(s):  # add it to the end
        return s + newstring

    # insert the new string between "slices" of the original
    return s[:index] + newstring + s[index + 1:]

This will work as

replacer("mystring", "12", 4)
'myst12ing'

The problem is that .replace(old, new) returns a copy of the string in which the occurrences of old have been replaced with new.

Instead, you can swap the character at index i using:

new_str = old_str[:i] + "b" + old_str[i+1:]

you can do

s="cdabcjkewabcef"
snew="".join((s[:9],"###",s[12:]))

which should be faster than joining like snew=s[:9]+"###"+s[12:] on large strings

The biggest problem with your code is that it's unreadable. Python code rule number one, if it's not readable, no one's gonna look at it for long enough to get any useful information out of it. Always use descriptive variable names. Almost didn't catch the bug in your code, let's see it again with good names, slow-motion replay style:

to_modify = [5,4,3,2,1,0]
indexes = [0,1,3,5]
replacements = [0,0,0,0]

for index in indexes:
    to_modify[indexes[index]] = replacements[index]
    # to_modify[indexes[index]]
    # indexes[index]
    # Yo dawg, I heard you liked indexes, so I put an index inside your indexes
    # so you can go out of bounds while you go out of bounds.

As is obvious when you use descriptive variable names, you're indexing the list of indexes with values from itself, which doesn't make sense in this case.

Also when iterating through 2 lists in parallel I like to use the zip function (or izip if you're worried about memory consumption, but I'm not one of those iteration purists). So try this instead.

for (index, replacement) in zip(indexes, replacements):
    to_modify[index] = replacement

If your problem is only working with lists of numbers then I'd say that @steabert has the answer you were looking for with that numpy stuff. However you can't use sequences or other variable-sized data types as elements of numpy arrays, so if your variable to_modify has anything like that in it, you're probably best off doing it with a for loop.