I will discuss the breathing dynamics of intermittent, local denaturation domains of DNA. These bubbles form already at room temperature and are implicated in transcription initiation. Based on single molecule fluorescence studies, it will be shown that the bubble dynamics is sensitive to the DNA sequence. I will discuss the interaction of the bubbles with proteins that selectively bind to single stranded DNA. Under different conditions, the protein binding is kinetically blocked, or can give rise to complete DNA denaturation. In the second part of the talk, I will discuss the role of DNA conformations in the target search process of binding proteins for their specific binding site on the DNA molecule.