It would depend on the number of unique values and the number of records in the table. If your just searching on whether or not a column is null or not, you'll probably have one query use it and one not depending on the amount of nulls in the table overall.
For example: If you have a table with 99% of the records have the querying column as null and you put/have an index on the column and then execute:
SELECT columnIndexed FROM blah WHERE columnIndexed is null;
The optimizer most likely won't use the index. It won't because it will cost more to read the index and then read the associated data for the records, than to just access the table directly. Index usage is based on the statistical analysis of a table, and one major player in that is cardinality of the values. In general, indexes work best and give the best performance when they select a small subset of the rows in the table. So if you change the above query to select where columnIndexed is not null, your bound to use the index.
For more details check out the following: http://dev.mysql.com/doc/refman/5.1/en/myisam-index-statistics.html