CSS Grid and Flexbox are both layout tools in CSS that allow developers to create complex layouts on a web page. The main difference between the two is that CSS Grid is a two-dimensional layout system, while Flexbox is a one-dimensional layout system. CSS Grid is best for creating complex layouts with multiple rows and columns, while Flexbox is best for creating simple layouts with a single row or column. When deciding which layout tool to use, it is important to consider the specific design needs of the website and choose the tool that best meets those needs.