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NULL values in databases require special handling because they represent absence of data, not empty values. MySQL uses three-valued logic (TRUE, FALSE, UNKNOWN) for NULL comparisons, meaning standard equality operators don't work. Laravel's Eloquent provides whereNull() and whereNotNull() methods for proper NULL handling. Common pitfalls include using != with NULL values, which excludes NULL rows unexpectedly. Best practices include using null coalescing operators in templates, setting default values in migrations when appropriate, indexing nullable columns for performance, and thoroughly testing nullable column scenarios.