Stores that can't keep up could be brought to reckoning by the end of this year, Wenig said.
"I'm not sure all the retailers are going to even make it, in a healthy economy, to this holiday season," Wenig said. "And I do think you are going to see drastic changes in store footprints and what stores do."
Department stores J.C. Penney, Macy's and Sears have collectively announced hundreds of store closures slated for this year. Amazon, meanwhile, had its best holiday shopping season ever.
Wenig said he doesn't think stores are completely going away, but that stores must be a "mini distribution center" to succeed.
"I think the complete death of stores has been greatly exaggerated," Wenig said. "The consumer wants stores. The entire world will not be online. But there are both capacity and utility issues in retail. People don't like poor store experiences."
EBay has challenges of its own. EBay was the original online marketplace, but is no longer the only one. The company now competes for shoppers dollars with Amazon, Walmart, Etsy and others.
Wenig has a number of strategies to capture consumers less familiar with what eBay can offer — from artificial intelligence bots, to new search technology.
On Monday, eBay announced that — starting this summer — it will guarantee three-day delivery on more than 20 million items in the U.S. Millions of those items will also come with free shipping and shoppers will be able to filter items by one-and two-day delivery.
"Most people shop eBay in their passions and their interests — as much as the things they need, the things they love," Wenig said. "But we know that there's a group of our buyer segment that want certainty. They want speed."
Then there are opportunities in emerging markets. An Indian news source, The Economic Times, reported that Indian e-commerce company Flipkart is in talks on a funding round of up to $1.5 billion with eBay and China's Tencent.
Wenig declined to comment on the rumor, but talked broadly about eBay's strategy in India.
"The Indian market is important to us," Wenig said. "We're always looking at the possibilities to win in every market we compete in. But eBay India is a major player in that market, and we are investing in it, and we'll continue to invest in it."
Meanwhile, eBay must wrestle with policy changes at home, including proposals of border taxes and immigration reform that critics say could hurt the retail industry. Wenig said he doesn't plan to be shy in his advocacy of responsible immigration and trade.
"I absolutely want the president of the United States to succeed," Wenig said. "I'm the CEO of an American business and I'm an American citizen. .... With that said, we're going to speak up about issues that for us, aren't about politics, they're about our business."
— with reporting from CNBC's Courtney Reagan, Lauren Thomas and Harriet Taylor.