ANSWER: DupeBlocker is designed to work for any single insert/update to Salesforce, including records inserted/updated directly through the Salesforce user interface and Web to Lead inserts. It will not trigger blocks or warnings for batch inserts/updates (e.g. third party API applications that process inserts/updates in batch mode, Salesforce Data Loader or Import Wizard), but the duplicate keys created to detect duplicates will be kept up to date.
The Import module in DemandTools 5.x can be used when uploading a spreadsheet to perform an upsert to Leads, Contacts, and Accounts (update any existing records and import just the new) that can help with duplicate prevention.
Note: UNABLE_TO_LOCK_ROW errors can occur when uploading data via the Salesforce Bulk API with parallel processing. DupeBlocker can be disabled before an upload then re-enabled after to avoid these errors. More information on disabling DupeBlocker can be found HERE .
KEYS WILL NEED TO BE REBUILT after the upload, since disabling DupeBlocker causes the keys to not be automatically built during the upload process. More information on this error can be found in the Validity Community Solution UNABLE_TO_LOCK_ROW Errors.