Natalie was married to Jeff Manning, who died after she got pregnant. She had a baby boy, Owen, and considered moving away from Chicago to be close to her parents as she felt alone, but decided against it in the end.
Natalie had some problems with work and Owen, as she couldn't be around to see him. It came up at several points, such as when she told Maggie to remind her to Facetime Owen before his nap while working, and when she got into an argument with a single mother over her working habits, which she then realised she was referring to her own 'failures' in not being around with Owen.
Natalie and Will also worked closely together on many cases, and this caused problems between Nina and Will. Will remained very close to Natalie, and the two usually ended up comforting each other after tough cases, which caused arguments with Nina. Nina was rightly jealous, and in the finale, Will decided to breakup with Nina. This was after he told Natalie they were just "good friends" when she said they were more than that.
Natalie works closely alongside Dr. Will Halstead with most of her patients and a result, they are very close. Will had feelings for her in Season 1 and he told her in Clarity but she wasn't ready to move on, so they left it as friends.
After Generation Gap, they began to get close to one another again, and this made Will's girlfriend, Nina, jealous. Then in Deliver Us, a small disagreement between the three led to Will apologising for Nina's behaviour towards Nat. Natalie replied saying that if she was Nina, she'd be jealous too. Will didn't understand and said they were just co-workers and good friends. Natalie asked if that was it, and Will said they're really good friends, and this upset her. He tried talking to her but she said he was right about being 'just friends', indicating that she felt differently about him now.
Maggie is one of Natalie's closest friends. They share everything and it was Maggie who has been helping her with Owen.
Jeff and Natalie started in Season 2. However, things started falling apart, after Jeff stood up for Nat in front of Dr. Stohl. She felt 'humiliated' by it though and some time later, he admitted that he and Jeff (Manning) had a fight after he said he had feelings for her. She was upset he didn't tell her this before and felt worse that she was with him as her husband had died, so they broke up. She told him they weren't right together. They remain friends.
Jay and Natalie aren't close by any means, as she only sees him when he comes to see Will. However, in Divide Us, Jay told Will they were going to a hockey game. Will turned him down when Jay came to pick him because of problems with Nina. Jay asked Natalie to come and she refused. He asked again and said Will turned him down. Upset with Will, she took him up on the offer and went with him.
In the finale, as Will had told Natalie he doesn't have feelings for her, which was a lie, she asked Jay to come with her this time to April's brothers party. Jay went to see Will and told him she asked, and Will was clearly uncomfortable with the idea, but told him he didn't mind them going together. Jay asked if he was "sure" he didn't mind, and Will replied he was fine, but clearly was upset. Jay said he'd tell Natalie he can't come, and then told Will to get his act together, referring to Nina and Natalie. Will broke up with Nina later and met up with Natalie at the party.